N-Hydroxy-2-(Alkyl, Aryl, or Heteroaryl, Sulfanyl, Sulfinyl or Sulfonyl)-3-Substituted Alkyl, Aryl or Heteroarylamides as Matrix Metalloproteinase inhibitors

ABSTRACT

Matrix metalloproteinases (MMPs) are a group of enzymes that have been implicated in the pathological destruction of connective tissue and basement membranes. These zinc containing endopeptidases consist of several subsets of enzymes including collagenases, stromelysins and gelatinases. TNF-α converting enzyme (TACE), a pro-inflammatory cytokine, catalyzes the formation of TNF-α from membrane bound TNF-α precursor protein. It is expected that small molecule inhibitors of MMPs and TACE therefore have the potential for treating a variety of disease states. The present invention provides low molecular weight, non-peptide inhibitors of matrix metalloproteinases (MMPs) and TNF-α converting enzyme (TACE) for the treatment of arthritis, tumor metastasis, tissue ulceration, abnormal wound healing, periodontal disease, bone disease, diabetes (insulin resistance) and HIV infection having the formula                    
     wherein R 2  and R 3  form a heterocyclic ring and A is S, S(O), or S(O) 2 , and R 1  and R 4  are defined herein.

This application is a divisional application of U.S. Ser. No.09/140,504, filed Aug. 26, 1998, now U.S. Pat. No. 6,197,791 which is aCIP of U.S. Ser. No. 09/026,372, filed Feb. 19, 1998 abandoned, whichclaims the benefit of prior U.S. Provisional application No. 60/038,899filed Feb. 27, 1997.

BACKGROUND OF THE INVENTION

Matrix metalloproteinases (MMPs) are a group of enzymes that have beenimplicated in the pathological destruction of connective tissue andbasement membranes. These zinc containing endopeptidases consist ofseveral subsets of enzymes including collagenases, stromelysins andgelatinases. Of these classes, the gelatinases have been shown to be theMMPs most intimately involved with the growth and spread of tumors. Itis known that the level of expression of gelatinase is elevated inmalignancies, and that gelatinase can degrade the basement membranewhich leads to tumor metastasis. Angiogenesis, required for the growthof solid tumors, has also recently been shown to have a gelatinasecomponent to its pathology. Furthermore, there is evidence to suggestthat gelatinase is involved in plaque rupture associated withatherosclerosis. Other conditions mediated by MMPPs are restenosis,MMP-mediated osteopenias, inflammatory diseases of the central nervoussystem, skin aging, tumor growth, osteoarthritis, rheumatoid arthritis,septic arthritis, corneal ulceration, abnormal wound healing, bonedisease, proteinuria, aneurysmal aortic disease, degenerative cartilageloss following traumatic joint injury, demyelinating diseases of thenervous system, cirrhosis of the liver, glomerular disease of thekidney, premature rupture of fetal membranes, inflammatory boweldisease, periodontal disease, age related macular degeneration, diabeticretinopathy, proliferative vitreoretinopathy, retinopathy ofprematurity, ocular inflammation, keratoconus, Sjogren's syndrome,myopia, ocular tumors, ocular angiogenesis/neo-vascularization andcorneal graft rejection. For recent reviews, see: (1) Recent Advances inMatrix Metalloproteinase Inhibitor Research, R. P. Beckett, A. H.Davidson, A. H. Drummond, P. Huxley and M. Whittaker, Research Focus,Vol. 1, 16-26, (1996), (2) Curr. Opin. Ther. Patents (1994) 4(1): 7-16,(3) Curr. Medicinal Chem. (1995) 2: 743-762, (4) Exp. Opin. Ther.Patents (1995) 5(2): 1087-110, (5) Exp. Opin. Ther. Patents (1995)5(12): 1287-1196.

TNF-α converting enzyme (TACE) catalyzes the formation of TNF-α frommembrane bound TNF-α precursor protein. TNF-α is a pro-inflammatorycytokine that is now thought to have a role in rheumatoid arthritis,septic shock, graft rejection, cachexia, anorexia, inflammation,congestive heart failure, inflammatory disease of the central nervoussystem, inflammatory bowel disease, insulin resistance and HI) infectionin addition to its well documented antitumor properties. For example,research with anti- TNF-α antibodies and transgenic animals hasdemonstrated that blocking the formation of TNF-α inhibits theprogression of arthritis. This observation has recently been extended tohumans as well.

It is expected that small molecule inhibitors of MMPs and TACE thereforehave the potential for treating a variety of disease states. While avariety of MMP and TACE inhibitors have been identified and disclosed inthe literature, the vast majority of these molecules are peptidic andpeptide-like compounds that one would expect to have bioavailability andpharmacokinetic problems common to such compounds that would limit theirclinical effectiveness. Low molecular weight, potent, long acting,orally bioavailable inhibitors of MMPs and/or TACE are therefore highlydesirable for the potential chronic treatment of the above mentioneddisease states.

Recently, two references have appeared (U.S. Pat. No. 5,455,258 andEuropean Patent Appl. 606,046) that disclose arylsulfonamido-substitutedhydroxyamic acids. These documents cover compounds exemplified by CGS27023A. These are the only non-peptide matrix metalloproteinaseinhibitors disclosed to date.

Salah et al., Liebigs Ann. Chem. 195, (1973) discloses some arylsubstituted thio and aryl substituted sulfonyl acetohydroxamic acidderivatives of general formula 1. These compounds were prepared to studythe Mannich reaction. Subsequently, they were tested for theirfungicidal activity.

Some sulfone carboxylic acids are disclosed in U.S. Pat. No. 4,933,367.Those compounds were shown to exhibit hypoglycemic activity.

SUMMARY OF THE INVENTION

The present invention relates to novel, low molecular weight,non-peptide inhibitors of matrix metalloproteinases (MMPs) and TNF-αconverting enzyme (TACE) for the treatment of arthritis, tumormetastasis, tissue ulceration, abnormal wound healing, periodontaldisease, bone disease, diabetes (insulin resistance) and HIV infection.

In accordance with this invention there is provided a group of compoundsof general formula I

wherein:

R¹ is alkyl of 1 to 18 carbon atoms, optionally substituted with one ortwo groups selected independently from R⁵;

alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionallysubstituted with one or two groups selected independently from R⁵;

alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, Optionallysubstituted with one or two groups selected independently from R⁵;

aryl of 6 to 10 carbon atoms, optionally substituted with one or twogroups selected independently from R⁵;

cycloalkyl of 3 to 8 carbon atoms, optionally substituted with one ortwo groups selected independently from R⁵;

saturated or unsaturated 5 to 10 membered mono or bicyclic heterocyclecontaining one heteroatom selected from O, S or NR⁷, optionallysubstituted with one or two groups selected independently from R⁵;

or heteroaryl-(CH₂)₀₋₆— wherein the heseroaryl group is 5 to 6 memberedwith one or two heteroatoms selected independently from O, S, and N andmay be optionally substituted with one or two groups selectedindependently from R⁵;

A is —S—,—SO— or SO₂—;

R² and R³, taken with the carbon atom to which they are attached, form a5 to 7 membered heterocyclic ring containing O, S or N—R⁷ optionallyhaving one or two double bonds;

R⁴ is hydrogen,

alkyl of 1 to 6 carbon atoms, Optionally substituted with one or twogroups selected independently from R⁵;

alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionallysubstituted with one or two groups selected independently from R⁵;

alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, Optionallysubstituted with one or two groups selected independently from R⁵;

phenyl or naphthyl optionally substituted with one or two groupsselected independently from R⁵; C₃ to C₈ cycloalkyl or bicycloalayloptionally substituted with one or two groups selected independentlyfrom R⁵;

saturated or unsaturated 5 to 10 membered mono or bicyclic heterocyclecontaining one heteroatom selected from O, S or NR⁷, optionallysubstituted with one or two groups selected independently from R⁵;

R⁵ is H, C₇-C₁₁ aroyl, C₂-C₆ alkanoyl, C₁ to C₁₂ alkyl, C₂ to C₁₂alkenyl, C₂-C₁₂ alkynyl, F, Cl, Br, I, CN, CHO, C₁-C₆ alkoxy, aryloxy,heteroaryloxy, C₃-C₆ alkenyloxy, C₃-C₆ alkynyloxy, C₁-C₆ alkoxyaryl,C₁-C₆ alkoxyheteroaryl, C₁-C₆ alkylamino-C₁-C₆ alkoxy, C₁-C₂ alkylenedioxy, aryloxy-C₁-c₆ alkyl amine, C₁-C₁₂ perfluoro alkyl, S(O)_(n)—C₁-C₆alkyl, S(O)_(n)-aryl where n is 0, 1 or 2; OCOO C₁-C₆ alkyl, OCOOaryl,OCONR⁶, COOH, COO C₁-C₆ alkyl, COOaryl, CONR⁶R⁶, CONHOH, NR⁶R⁶,SO₂NR⁶R⁶, NR⁶SO₂aryl, —NR⁶CONR⁶R⁶, NHSO₂CF₃, SO₂NHheteroaryl,SO₂NHCOaryl, CONHSO₂—C₁-C₆ alkyl, CONHSO₂aryl, SO₂NHCOaryl,CONHSO₂—C₁-C₆ alky, CONHSO₂aryl, NH₂, OH, aryl, heteroaryl, C₃ to C₈cycloalkyl; or saturated or unsaturated 5 to 10 membered mono orbicyclic heterocycle containing one heteroatom selected from O, S orNR⁷, wherein C₁-C₆ alkyl is straight or branched, heteroaryl is a 5-10membered mono or bicyclic heteroaryl group having 1 to 3 heteroatomsselected independently from O, S or NR⁷ and aryl is phenyl or naphthyl,optionalky substituted by 1 or 2 groups selected from halogen, cyano,amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, or hydroxy;

R⁶ is H, C₁ to C₁₈ alkyl optionalky substituted with OH; C₃ to C₆alkenyl, C₃ to C₆ alkynyl, C₁ to C₆ perfluoro alkyl, S(O)_(n)—C₁-C₆alkyl S(O)_(n) aryl where n is 0, 1 or 2;

or COheteroaryl, wherein heteroaryl is a 5-10 membered mono or bicyclicheteroaryl group having 1 to 3 heteroatoms selected independently fromO, S or NR⁷ and aryl is phenyl or naphthyl, optionalky substituted by 1or 2 groups selected from halogen, cyano, amino, nitro, C₁-C₆ alkyl,C₁-C₆ alkoxy, or hydroxy;

and R⁷ is C₇-C₁₁ aroyl, C₂-C₆ alkanoyl, C₁-C₁₂ perfluoro alkyl,S(O)_(n)—C₁-C₆-alkyl, S(O)_(n)—aryl where n is 0, 1 or 2;COO—C₁-C₆-alkyl, COOaryl, CONHR⁶, CONR⁶R⁶, CONHOH, SO₂NR⁶R⁶, SO₂CF₃,SO₂NEheteroaryl, SO₂NHCOaryl, CONHSO—C₁-C₆-alkyl, CONHSO₂aryl, aryl, orheteroaryl, where aryl is phenyl or naphthyl, optionalky substituted by1 or 2 groups selected independently from halogen, cyano, amino, nitro,C₁-C₆ alkyl, C₁-C₆ alkoxy, or hydroxy; and heteroaryl is a 5-10 memberedmono or bicyclic heteroaryl group having 1 to 3 heteroatoms selectedindependently from O, S or N—C₁-C₆ alkyl;

alkyl of 1 to 18 carbon atoms, optionalky substituted with one or twogroups selected independently from R⁵;

alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds,optionally substituted with one or two groups selected independentlyfrom R⁵;

alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds,optionally substituted with one or two groups selected independentlyfrom R⁵;

arylalkyl of 7 to 16 carbon atoms, wherein aryl is optionallysubstituted with one or two groups selected independently from R⁵;

heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroarylcontains 1 or 2 heteroatoms selected from O, S or N and is optionallysubstituted with one or two groups selected independently from R⁵;

biphenylalkyl of 13 to 18 carbon atoms, wherein biphenyl is optionallysubstituted with one or two groups selected independently from R⁵;

arylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionallysubstituted with one or two groups selected independently from R⁵;

cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, whereinthe cycloalkyl or bicycloalkyl group is optionally substituted with oneor two groups selected independently from R⁵;

saturated or unsaturated mono or bicyclic heterocycle containing oneheteroatom selected from O, S or N—C₁-C₆ alkyl, optionally substitutedwith one or two groups selected independently from R⁵; or

R⁸R⁹N—C₁-C₆-alkoxyaryl-C₁-C₆-alkyl where R⁸ and R⁹ are independentlyselected from C₁-C₆ alkyl or R⁸ and R⁹ together with the interposednitrogen forms a 5-7 membered saturated heterocyclicing optionallycontaining an oxygen atom, wherein the aryl group is phenyl or naphthyl;

and the pharmaceutically acceptable salts thereof.

A more preferred aspect of the present invention is the group ofcompounds of general formula (Ia):

wherein:

R¹ is alkyl of 1 to 18 carbon atoms, optionally substituted with one ortwo groups selected independently from R⁵;

alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionallysubstituted with one or two groups selected independently from R⁵;

alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionallysubstituted with one or two groups selected independently from R⁵;

aryl of 6 to 10 carbon atoms, optionally substituted with one to twogroups selected independently from R⁵;

cycloalkyl of 3 to 8 carbon atoms, optionally substituted with one totwo groups selected independently from R⁵;

saturated or unsaturated mono or bicyclic heterocycle of from 5 to 10members containing one heteroatom selected from O, S or NR⁷, optionallysubstituted with one to two groups selected independently from R⁵;

or heteroaryl-(CH₂)₀₋₆— wherein the heteroaryl group is 5 to 6 memberedwith one or two heteroatoms selected independently from O, S, and N andmay be optionally substituted with one or two groups selectedindependently from R⁵;

A is —S—, —SO— or SO₂—;

R² and R³, taken with the carbon atom to which they are attached, form a5 to 7 membered heterocyclic ring containing O, S or N—R⁷ optionallyhaving one or two double bonds;

R⁴ is hydrogen,

alkyl of 1 to 6 carbon atoms, optionally substituted with one or twogroups selected independently from R⁵;

alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionallysubstituted with one or two groups selected independently from R⁵;

alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionallysubstituted with one or two groups selected independently from R⁵;

phenyl or naphthyl optionally substituted with one or two groupsselected independently from R⁵;

C₃ to C₈ cycloalkyl or bicycloalkyl optionally substituted with one ortwo groups selected independently from R⁵;

R⁵ is H, F, Cl, Br, I, CN, CHO, C₇-C₁₁ aroyl, C₂-C₆ alkanoyl, C₁ to C₁₂alkyl, C₂ to C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₁-C₆ alkoxy, aryloxy,heteroaryloxy, C₃-C₆ alkenyloxy, C₃-C₆ alkynyloxy, C₁-C₆ alkoxyaryl,C₁-C₆ alkoxyheteroaryl, C₁-C₆-alkylamino-C₁-C₆ alkoxy, C₁-C₂-alkylenedioxy, aryloxy-C₁-C₆ alkyl amine, C₁-C₁₂ perfluoro alkyl, S(O)_(n)—C₁-C₆alkyl, S(O)_(n)-aryl where n is 0, 1 or 2; OCOO—C₁-C₆ alkyl, OCOOaryl,OCONR⁶, COOH, COO—C₁-C₆ alkyl, COOaryl, CONR⁶R⁶, CONHOH, NR⁶R⁶,SO₂NR⁶R⁶, NR⁶SO₂aryl, NR⁶CONR⁶R⁶, NHSO₂CF₃, SO₂NHheteroaryl,SO₂NHCOaryl, CONHSO₂—C₁-C₆ alkyl, CONHSO₂aryl, SO₂NHCOaryl,CONHSO₂—C₁-C₆ alkyl, CONHSO₂aryl, NH₂, OH, aryl, heteroaryl, C₃ to C₈cycloalkyl; or saturated or unsaturated 5 to 10 membered mono orbicyclic heterocycle containing one heteroatom selected from O, S orNR⁷;

wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl grouphaving 1 to 3 heteroatoms selected independently from O, S or NR⁷ andaryl is phenyl or naphthyl, optionally substituted by 1 or 2 groupsselected independently from halogen, cyano, amino, nitro, C₁-C₆ alkyl,C₁-C₆ alkoxy, or hydroxy;

R⁶ is H, C₁ to C₁₈ alkyl optionally substituted with OH; C₃ to C₆alkenyl, C₃ to C₆ alknyl, C₁ to C₆ perfluoro alkyl, S(O)_(n) alkyl oraryl where n is 0, 1, or 2; or COheteroaryl;

wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl grouphaving 1 to 3 heteroatoms selected independently from O, S or NR⁷ andaryl is phenyl or naphthyl, optionally substituted by 1 or 2 groupsselected from halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy,or hydroxy;

and R⁷ is C₇-C₁₁ aroyl, C₂-C₆ alkanoyl, C₁-C₁₂ perfluoro alkyl,S(O)_(n)-alkyl, S(O)_(n)—aryl where n is 0, 1 or 2; COOalkyl, COOaryl,CONHR⁶, CONR⁶R⁶, CONHOH, SO₂NR⁶R⁶,SO₂CF₃, SO₂NHheteroaryl, SO₂NHCOaryl,CONHSO₂alkyl, CONHSO₂aryl, aryl, heteroaryl; wherein C₁-C₆ alkyl isstraight or branched, heteroaryl is a 5-10 membered mono or bicyclicheteroaryl group having 1 to 3 heteroatoms selected independently fromO, S or NR⁷ and aryl is phenyl or naphthyl, optionally substituted by 1or 2 groups selected from halogen, cyano, amino, nitro, C₁-C₆ alkyl,C₁-C₆ alkoxy, or hydroxy;

alkyl of 1 to 18 carbon atoms, optionally substituted with one or twogroups selected independently from R⁵;

alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds,optionally substituted with one or two groups selected independentlyfrom R⁵;

alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds,optionally substituted with one or two groups selected independentlyfrom R⁵;

arylalkyl of 7 to 16 carbon atoms, wherein aryl is optionallysubstituted with one or two groups selected independently from R⁵;

heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroarylcontains 1 or 2 heteroatoms selected from O, S or N and is optionallysubstituted with one or two groups selected independently from R⁵;

biphenylalkyl of 13 to 18 carbon atoms, wherein biphenyl is optionallysubstituted with one or two groups selected independently from R⁵;

arylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionallysubstituted with one or two groups selected independently from R⁵;

cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, whereincycloalkyl or bicycloalkyl is optionally substituted with one or twogroups selected independently from R⁵;

saturated or unsaturated mono or bicyclic heterocycle containing oneheteroatom selected from O, S or N—C₁-C₆ alkyl, optionally substitutedwith one or two groups selected independently from R⁵;

R⁸R⁹N—C₁-C₆-alkoxyaryl-C₁-C₆-alkyl where R⁸ and R⁹ are independentlyselected from C₁-C₆ alkyl or R⁸ and R⁹ together with the interposednitrogen forms a 5-7 membered saturated heterocyclic ring optionallycontaining an oxygen atom, wherein the aryl group is phenyl or naphthyl;

and the pharmaceutically acceptable salts thereof.

The most preferred group of compounds are those of the following formula(Ib):

in which

R¹ is phenyl, naphthyl, alkyl of 1-18 carbon atoms or heteroaryl such aspyridyl, thienyl, imidazolyl or furanyl, optionally substituted withC₁-C₆ alkyl, C₁-C₆ alkoxy, C₆-C₁₀ aryloxy, heteroaryloxy, C₃-C₆alkenyloxy, C₃-C₆ alkynyloxy, halogen; or S(O)_(n)—C₁-C₆alkyl C₁-C₆alkoxyaryl or C₁-C₆ alkoxyheteroaryl;

A is —S—, —SO— or —SO₂—;

R² and R³, taken with the carbon atom to which they are attached, form a5 to 7 membered heterocyclic ring containing O, S or N—R⁷ optionallyhaving one or two double bonds;

R⁴ is hydrogen,

alkyl of 1 to 6 carbon atoms, optionally substituted with one or twogroups selected independently from R⁵;

alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionallysubstituted with one or two groups selected independently from R⁵;

alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionallysubstituted with one or two groups selected independently from R⁵;

phenyl or naphthyl optionally substituted with one or two groupsselected independently from R⁵;

C₃ to C₈ cycloalkyl or bicycloalkyl optionally substituted with one ortwo groups selected independently from R⁵;

R⁵ is H, C₇-C₁₁ aroyl, C₂-C₆ alkanoyl, C₁ to C₁₂ alkyl, C₂ to C₁₂alkenyl, C₂-C₁₂ alkynyl, F, Cl, Br, I, CN, CHO, C₁-C₆ alkoxy, aryloxy,heteroaryloxy, C₃-C₆ alkenyloxy, C₃-C₆ alkynyloxy, C₁-C₆alkylamino-C₁-C₆ alkoxy, C₁-C₂ alkylene dioxy, aryloxy-C₁-C₆ alkylamine, C₁-C₁₂ perfluoro alkyl, S(O)_(n)—C₁-C₆ alkyl, S(O)_(n)— arylwhere n is 0, 1 or 2; OCOO C₁-C₆ alkyl, OCOOaryl, OCONR⁶, COOH, COOC₁-C₆ alkyl, COOaryl, CONR⁶R⁶, CONHOH, NR⁶R⁶, SO₂NR⁶R⁶, NR⁶SO₂aryl,—NR⁶CONR⁶R⁶, NHSO₂CF₃, SO₂NHheteroaryl, SO₂NHCOaryl, CONHSO₂—C₁-C₆alkyl, CONHSO₂aryl, SO₂NHCOaryl, CONHSO₂—C₁-C₆ alkyl, CONHSO₂aryl, NH₂,OH, aryl, heteroaryl, C₃ to C₈ cycloalkyl; saturated or unsaturated 5 to10 membered mono or bicyclic heterocycle containing one heteroatomselected from O, S or NR⁷, wherein C₁-C₆ alkl is straight or branched,heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1to 3 heteroatoms selected independently from O, S or NR⁷ and aryl isphenyl or naphthyl, optionally substituted by 1 or 2 groups selectedfrom halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, orhydroxy;

R⁶ is H, C₁ to C₁₈ alkyl optionally substituted with OH; C₃ to C₆alkenyl, C₃ to C₆ allnyl, C₁ to C₆ perfluoro alkyl, S(O)_(n) alkyl oraryl where n is 0, 1 or 2; or COheteroaryl; wherein heteroaryl is a 5-10membered mono or bicyclic heteroaryl group having 1 to 3 heteroatomsselected independently from O, S or NR⁷ and aryl is phenyl or naphthyl,optionally substituted by 1 or 2 groups selected from halogen, cyano,amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, or hydroxy;

and R⁷ is C₇-C₁₁ aroyl, C₂-C₆ alkanoyl, C₁-C₁₂ perfluoro alkyl,S(O)_(n)-alkyl, S(O)_(n)-aryl where n is 0, 1 or 2; COOalkyl, COOaryl,CONHR⁶, CONR⁶R⁶, CONHOH, SO₂NR⁶R⁶,SO₂CF₃, SO₂NHheteroaryl, SO₂NHCOaryl,CONHSO₂alkyl, CONHSO₂aryl, aryl, or heteroaryl; where aryl is phenyl ornaphthyl, optionally substituted by 1 or 2 groups selected independentlyfrom halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, orhydroxy; and heteroaryl is a 5-10 membered mono or bicyclic heteroarylgroup having 1 to 3 heteroatoms selected independently from O, S orN—C₁-C₆ alkyl;

alkyl of 1 to 18 carbon atoms, optionally substituted with one or twogroups selected independently from R⁵;

alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds,optionally substituted with one or two groups selected independentlyfrom R⁵;

alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds,optionally substituted with one or two groups selected independentlyfrom R⁵;

arylalkyl of 7 to 16 carbon atoms, optionally substituted with one ortwo groups selected independently from R⁵;

heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroarylcontains 1 or 2 heteroatoms selected from O, S or N and is optionallysubstituted with one or two groups selected independently from R⁵;

biphenylalkyl of 13 to 18 carbon atoms, optionally substituted with oneor two groups selected independently from R⁵;

arylalkenyl of 8 to 16 carbon atoms, optionally substituted with one ortwo groups selected independently from R⁵;

cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, optionallysubstituted with one or two groups selected independently from R⁵;

saturated or unsaturated mono or bicyclic heterocycle containing oneheteroatom selected from O, S or NR—C₁-C₆ alkyl, optionally substitutedwith one or two groups selected independently from R⁵;

R⁸R⁹N—C₁-C₆-alkoxyaryl-C₁-C₆-alkyl where R⁸ and R⁹ are independentlyselected from C₁-C₆ alkyl or R⁸ and R⁹ together with the interposednitrogen forms a 5-7 membered saturated heterocyclic ring optionallycontaining an oxygen atom, wherein the aryl group is phenyl or naphthyl;

and the pharmaceutically acceptable salts thereof.

The most preferred matrix metalloproteinase and TACE inhibitingcompounds of this invention are:

1-benzyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide,

4-(4methoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine4carboxylicacid hydroxyamide,

1-(3,4-dichlorobenzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid hydroxamide,

4-(4-methoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylicacid hydroxamide,

4-(4-methoxy-benzene-sulfonyl)-1-napthalene-2-yl-methypiperidine-4-carboxylicacid hydroxamide,

1-biphenyl-4-ylmethyl-4-(4-methoxy-benzenesulfonyl)piperidine-4-carboxylicacid hydroxamide,

4-(4-methoxy-benzene-sulfonyl)-1-(3-methyl-but-2-enyl)piperidine-4-carboxylicacid hydroxarmide,

1-(4-bromo-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid hydroxyamide,

4-(4-methoxy-benzenesulfonyl)-1-(3-phenyl-propyl)-piperidine-4-carboxylicacid hydroxyamide,

1-tert-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide,

1-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide,

1-cyclooctyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide,

1-ethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide,

1-isopropyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide,

1-methyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide,

1-benzyl4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide,

1-(4-fluoro-benzyl)-4-(4methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid hydroxyamide,

1-(4-fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylicacid hydroxyamide,

4-(4-methoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4-carboxyicacid hydroxyamide,

4-(4-methoxy-benzenesulfonyl)-1-[2-(4-methoxyphenyl)-ethyl]-piperidine-4-carboxylicacid hydroxyamide,

4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidine-4-carboxylicacid hydroxyamide,

4-(4-n-butoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4-carboxylicacid hydroxyamide,

4-(4-methoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylicacid hydroxyamide,

4-(4-n-butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylicacid hydroxyamide,

4-(4-methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylicacid hydroxyamide,

4-(4n-butoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylicacid hydroxyamide,

4-(4-methoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidin-4-carboxylicacid hydroxyamide,

1-Benzyl-4-(4-benzyloxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide,

4-(4-Butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-pipendine-4-carboxylicacid hydroxyamide,

4-(4-Butoxy-benzenesulfonyl)-1-[3-(2-morpholinyl-1-yl-ethoxy)-benzyl]-piperidine-4carboxylicacid hydroxyamide,

1-Methyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide,

1-Ethyl4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide,

1-n-Butyl4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide,

4-[4-(4chloro-phenoxy)-benzenesulfonyl]1-methyl-piperidine-4-carboxylicacid hydroxyamide,

4-[4-(4-chloro-phenoxy)-benzenesulfonyl]1-ethyl-piperidine-4-carboxylicacid hydroxyamide,

1-Butyl4-[4-(4chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid hydroxyamide,

1-Benzyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid hydroxyamide,

1-Benzyl-4-[4-3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid hydroxyamide,

1-Butyl4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid hydroxyamide,

1-Benzyl-4-[4-(4-(2ethyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid hydroxyamide,

4-(4-butoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylicacid hydroxyamide,

4-(4Methoxy-benzenesulfonyl)-1-(4-thiophen-2-yl-benzyl)-piperidine-4-carboxylicacid hydroxyamide,

4-(4-methoxy-benzenesulfonyl)-1-(4-pyridin-2-yl-benzyl)-piperidine-4-carboxylicacid hydroxyamide,

1-(3,4-dichlorobenzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylicacid hydroxyamide,

[4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-methylpiperidine-4-carboxylicacid hydroxamide,

4-(4-Butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)-piperidine-4-carboxylicacid hydroxamide,

[4-(4Chloro-benzyloxy)-benzenesulfonyl]-1-(4-methylbenzyl)-piperidine-4-carboxylicacid hydroxamide,

4-(4Butoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4carboxylicacid hydroxamide,

4-(4-Butoxy-benzenesulfonyl)-1-(4-cyano-benzyl)-piperidine-4-carboxylicacid hydroxamide, and

4-(4-Butoxy-benzenesulfonyl)-1-pyridin-4ylmethyl-piperidine-4-carboxylicacid hydroxamide, and pharmaceutical salts thereof.

It is understood that the definition of the compounds of formulas I, Iaand Ib, when R¹, R², R³ and R⁴ contains asymmetric carbons, encompassall possible stereoisomers and mixtures thereof which posses theactivity discussed below. In particular, it encompasses racemicmodifications and any optical isomers which possesses the indicatedactivity. optical isomers may be obtained in pure form by standardseparation techniques. Where not stated otherwise, the term “alkyl”refers to a straight or branched C₁-C₆ alkyl group and aryl is phenyl ornaphthyl. The pharmaceutically acceptable salts are those derived frompharmaceutically acceptable organic and inorganic acids such as lactic,citric, acetic, tartaric, succinic, maleic, malonic, hydrochloric,hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, andsimilarly known acceptable acids.

The present invention accordingly provides a pharmaceutical compositionwhich comprises a compound of this invention in combination orassociation with a pharmaceutically acceptable carrier. In particular,the present invention provides a pharmaceutical composition whichcomprises an effective amount of compound of this invention and apharmaceutically acceptable carrier.

The compositions are preferably adapted for oral administration.However, they may be adapted for other modes of administration, forexample, parenteral administration for patients.

In order to obtain consistency of administration, it is preferred that acomposition of the invention is in the form of a unit dose. Suitableunit dose forms include tablets, capsules, and powders in sachets orvials, Such unit dose forms may contain from 0.1 to 100 mg of a compoundof the invention. The compounds of the present invention can beadministered orally at a dose range of about 0.01 to 100 mg per kg. Suchcomposition may be administered from 1 to 6 times a day, more usuallyfrom 1 to 4 times a day.

The compositions of the invention may be formulated with conventionalexcipients, such as fillers, a disintegrating agent, a binder, alubricant, a flavoring agent, and the like. They are formulated inconventional manner.

Also according to the present invention, there are provided processesfor producing the compounds of the present invention.

PROCESS OF THE INVENTION

The compounds of the present invention may be prepared according to oneof the general processes out lined below.

The appropriately substituted mercaptan derivative was alkylated usingeither substituted (Scheme I) or unsubstituted (Scheme 2) α-bromo aceticacid ester derivative in refluxing acetone using K₂CO₃ as base. Thesulphide derivative thus obtained was oxidized using m-chloroperbenzoicacid in CH₂Cl₂ or by using Oxone in methanol/water. The sulfone obtainedfrom the above mentioned process can be either further alkylated usingvariety of alkyl halides to obtain the disubstituted derivative or itcan be hydrolyzed using NaOH/MeOH at room temp. However instead of usingthe ethyl ester, if the tertiary butyl ester is present, the hydrolysiscan be carried out with TFA/CH₂Cl₂ at room temperature. Subsequently,the carboxylic acid obtained was converted to the hydroxamic acidderivative by reaction with oxalyl chloride/DMX (catalytic) and hydroxylamine/triethyl amine.

As outlined in Scheme 3, the sulfide derivative can be further alkylatedusing lithium bis(trimethyl silyl)amide in THF at 0° C. The alkylated ormono substituted compound was hydrolyzed and converted to the hydroxamicacid derivative. The sulfinyl derivatives were prepared by oxidizing thesulfide hydroxamic acid derivatives with H₂O₂ in MeOH solution.

The corresponding1-substituted-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamides were prepared starting from diethanolamine andappropriately substituted alkyl or aryl halides (Scheme 4). TheN-substituted diethanol amine derivatives were converted to the dichlorocompounds using thionyl chloride. The corresponding dichlorides werereacted with substituted sulfonyl acetic acid ethyl ester derivatives inthe presence of K₂CO₃/18-Crown-6 in boiling acetone.1-substituted-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidethyl esters thus obtained were converted to the hydroxy amide asoutlined in Scheme 4. Alternatively these classes of compounds and otherhetrocycles can be prepared as indicated in Scheme 5 and 6.

Alternatively, Schemes 7 to 11 show methods for the preparation ofhydroxamic acid compounds using a solid phase support (P).

Reagents and Conditions: a) 2-Halo acid (3.0 eq.);1-hydroxybenzotriazole hydrate (HOBt, 6.0 eq.);1,3-diisopropylcarbodiimide (DIC, 4.0 eq.); DMF, 25° C.; 2-16 hours. b)Thiol (5.0 eq.); sodium iodide (5.0 eq.);1,8-diazabicyclo[5.4.0]undec-7ene (DBU, 3.0 eq.); THF; 25° C.; 12-16hours. c) 70% tert-butylhydroperoxide (40 eq.); benzenesulfonic acid(2.0 eq.); DCM; 25° C.; 12-24 hours. d) mCPBA (5.0 eq.); DCM; 25° C.;12-24 hours. e) TFA: DCM (1:1); 25° C.; 1 hour.

The4-O-methylhydroxylamine-phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin(hydroxylamine resin) may be coupled with a 2-halo acid to give thehydroxamate ester resin. The coupling reaction may be carried out in thepresence of carbodimide, such as DIC, in an inert solvent such as DMF atroom temperature. The halogen group may be displaced with a thiol in thepresence of a base, such as DBU, in an inert solvent such as THF at roomtemperature. The sulfide may be oxidized to the sulfoxide by reactionwith an oxidizing agent such as tert-butylhydroperoxide in the presenceof an acid catalyst such as benzenesulfonic acid, in an inert solventsuch as DCM at room temperature. Alternatively, the sulfide may beoxidized to the sulfone by reaction with an oxidizing agent such asmeta-chloroperoxybenzoic acid, in an inert solvent such as DCM at roomtemperature. The sulfide, sulfoxide, or sulfone may be treated with andacid, such as trifluoroacetic acid, in and inert solvent such as DCM toliberate the free hydroxamic acid.

Scheme 8 shows a method of preparing hydroxamic acids having alkoxygroups attached to the aromatic ring.

Reagents and Conditions: a) 2-Halo acid (3.0 eq.);1-hydroxybenzotriazole hydrate (HOBt, 6.0 eq.);1,3-diisopropylcarbodiimide (DIC, 4.0 eq.); DMF, 25° C.; 2-16 hours. b)4-Fluorobenzenethiol (5.0 eq.); sodium iodide (5.0 eq.);1,8diazabicyclo[5.4.0]undec-7ene (DBU, 3.0 eq.); THF; 25° C.; 12-16hours. c) Alcohol (15.0 eq.); sodium hydride (15.0 eq.); DMF; 80° C.; 15hours. d) 70% tert-butylhydroperoxide (40 eq.); benzenesulfonic acid(2.0 eq.); DCM; 25° C.; 12-24 hours. e) mCPBA (5.0 eq.); DCM; 25° C.;12-24 hours. f) TFA: DCM (1:1); 25° C.; 1 hour.

The hydroxylamine resin may be coupled with the 2-halo acid and the halogroup may be displaced by fluorobenzenethiol as previously described.The fluoro group may then be displaced with an alcohol in the presenceof a base such as sodium hydride, in an inert solvent such as DMF atabout 80° C. The alkoxybenzenesulfanyl hydroxamate ester may then beoxidized either to the corresponding sulfinyl or sulfonyl hydroxamateester as previously described. The free hydroxamic acids may beliberated as previously described.

Scheme 9 shows a method of preparing 2-bisarylsulfanyl-, sulfinyl-, andsulfonylhydroxamic acids.

Reagents and Conditions: a) 2-Halo acid (3.0 eq.); 1-hydroxybenzotiazolehydrate (HOBt, 6.0 eq.); 1,3-diisopropylcarbodiimide (DIC, 4.0 eq.);DMF, 25° C.; 2-16 hours. b) 4-Bromobenzenethiol (5.0 eq.); sodium iodide(5.0 eq.); 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 3.0 eq.); THF; 25°C.; 12-16 hours. c) 70% tert-butylhydroperoxide (40 eq.);benzenesulfonic acid (2.0 eq.); DCM; 25° C.; 12-24 hours. d) mCPBA (5.0eq.); DCM; 25° C.; 12-24 hours. e) Arylboronic acid (2.0 eq.);tetrakis(triphenylphosphine)palladium(0) (0.1eq.); 10% aqueous sodiumcarbonate (10.0 eq.); DME; 80° C.; 8 hours. f) TFA: DCM (1:1); 25° C.; 1hour.

The hydroxylamine resin may be coupled with the 2-halo acid and the halogroup may be displaced by bromobenzenethiol as previously described. Thebromobenzenesulfanyl hydroxamate ester may then be oxidized either tothe corresponding sulfinyl or sulfonyl hydroxamate ester as previouslydescribed. The bromo group may then be replaced with an aryl group byreaction with the arylboronic acid in the presence of a catalyst such astetrakis(triphenylphosphine) palladium(0), and a base such as sodiumcarbonate, in an inert solvent such as DME at about 80° C. The freehydroxamic acids may be liberated as previously described.

Scheme 10 shows a method of preparing hydroxamic acids having aminegroups attached to the aromatic ring.

Reagents and Conditions: a) 2-Halo acid (3.0 eq.);1-hydroxybenzotriazole hydrate (HOBt, 6.0 eq.);1,3-diisopropylcarbodiimide (DIC, 4.0 eq.); DMF, 25° C.; 2-16 hours. b)4-Bromobenzenethiol (5.0 eq.); sodium iodide (5.0 eq.);1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 3.0 eq.); THF; 25° C.; 12-16hours. c) Amine (20.0 eq.); tris(dibenzylideneacetone)-dipalladium(0)(0.2 eq.); (S)-(−)-2,2′-bis(diphenylphosphimo)-1,1′-binaphthyl((S)-BINAP, 0.8 eq.); sodium tert-butoxide (18.0 eq.); dioxane; 80° C.,8 hours; d) TFA : DCM (1:1); 25° C.; 1 hour.

The hydroxylamine resin may be coupled with the 2-halo acid and the halogroup may be displaced by bromobenzenethiol as previously described. Thebromo group may then be displaced with an amine in the presence of acatalyst such as tris(dibenzylideneacetone)-dipalladium(0) and a ligandsuch as (S)-BINAP and a base such as sodium tert-butoxide, in an inertsolvent such as dioxane at about 80° C. The free hydroxamic acids may beliberated as previously described.

Scheme 11 shows a method of preparing hydroxamic acids having sulfonategroups attached to the aromatic ring.

Reagents and Conditions: a) 2-Halo acid (3.0 eq.);1-hydroxybenzotriazole hydrate (HOBt, 6.0 eq.);1,3-diisopropylcarbodiimide (DIC, 4.0 eq.); DMF, 25° C.; 2-16 hours. b)4-Hydroxybenzenethiol (5.0 eq.); sodium iodide (5.0 eq.);1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 3.0 eq.); THF; 25° C.; 12-16hours. c) Sulfonyl chloride (5.0 eq.); triethylamine (2.0 eq.); DCM; 25°C.; 8 hours. d) 70% tert-butylhydroperoxide (40 eq.); benzenesulfonicacid (2.0 eq.); DCM; 25° C.; 12-24 hours. e) mCPBA (5.0 eq.); DCM; 25°C.; 12-24 hours. f) TFA: DCM (1:1); 25° C.; 1 hour.

The hydroxylamine resin may be coupled with the 2-halo acid and the halogroup may be displaced by hydroxybenzenethiol as previously described.The hydroxybenzenesulfanyl hydroxamate ester may then be oxidized eitherto the corresponding sulfinyl or sulfonyl hydroxamate ester aspreviously described. The hydroxy group may then be sulfonylated byreaction with a sulfonyl chloride in the presence of a base such astriethylamine, in an inert solvent such as DCM at about roomtemperature. The free hydroxamic acids may be liberated as previouslydescribed.

The following examples are presented to illustrate rather than limit thescope of the invention. HPLC purity of compounds prepared bycombinatorial procedures is presented as area percentage at a prescribedwavelength (% @ nm).

EXAMPLE 1N-Hydroxy-2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionamide

To stirred solution of 4-methoxybenzenethiol (2.8 gm, 20 mmol) andanhydrous K₂CO₃ (10 gm, excess) in dry acetone (100 ml), ethyl2-bromo-propionate (3.6 gm, 20 mmol) was added in a round bottom flaskand the reaction mixture was heated at reflux for 8 hours with goodstirring. At the end, reaction was allowed to cool and the potassiumsalts were filtered off and the reaction mixture was concentrated. Theresidue was extracted with chloroform and washed with H₂O and 0.5 N NaOHsolution. The organic layer was further washed well with water, driedover MgSO₄, filtered and concentrated to afford2-(4-methoxy-phenylsulfanyl)-propionic acid ethyl ester as a lightyellow oil. Yield 4.5 gms (94%); MS; 241 (M+H)⁺.

To a stirred solution of 2-(4-methoxy-phenylsulfanyl)-propionic acidethyl ester (2.44 g, 10 mmol), in THF (100 ml) at −4° C., lithiumbis(trimethylsilyl)amide (1 M solution, 15 ml, 15 mmol) was addedslowly. The orange colored reaction mixture was stirred at roomtemperature for 15 minutes and then it was cooled to 0° C. at which timeit was stirred for an additional hour.

The temperature of the mixture was again brought to −40° C. andbenzylbromide (1.72 gm, 10 mmol) was added dropwise in THF. The reactionwas warmed to room temperature and stirred overnight before it wasquenched with ice water, extracted with chloroform and washed withwater. The organic layer was dried over MgSO₄, filtered and concentratedand chromatographed on a silica-gel column with 10% ethyl acetate:hexaneto afford 2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionic acidethyl ester as a colorless oil. Yield: 860 mg, (26%); MS: 331 (M+H)⁺.

2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionic acid ethylester (4.12 g, 12 mmol) dissolved in methanol (50 ml) and 10 N NaOH (20ml) was added. The reaction was allowed to stir overnight at roomtemperature. The reaction mixture was concentrated, diluted with 1:1hexane:diethyl ether and extracted with H₂O. The water layer was cooledwith ice and acidified to pH 3. The acid was then extracted withchloroform and the organic layer was dried over MgSO₄, filtered andconcentrated to afford of2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionic acid as a lowmelting solid. Yield 580 mg, 16%; MS: 303.2 (M+H)⁺.

To a stirred solution of2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionic acid (0.5 g,1.65 mmol) and DMF (2 drops) in CH₂Cl₂ (100 ml) at 0° C., oxalylchloride (1.0 gm, 8 mmol) was added in a drop-wise manner. After theaddition, the reaction mixture was stirred at room temperature for 1hour. Simultaneously, in a separate flask a mixture of hydroxylaminehydrochloride (2.0 gm, 29 mmol) and triethylamine (5 ml, excess) wasstirred in THF:water (5:1, 30 ml) at 0° C. for 1 hour. At the end of 1hour, the oxalyl chloride reaction mixture was concentrated and the paleyellow residue was dissolved in 10 ml of CH₂Cl₂ and added slowly to thehydroxylamine at 0° C. The reaction mixture was stirred at roomtemperature for 24 hours and concentrated. The residue obtained wasextracted with chloroform and washed well with water. The productobtained was purified by silica gel column chromatography and elutedwith ethyl acetate. TheN-hydroxy-2-(4-methoxyphenylsulfanyl)-2-methyl-3-phenyl-propionamide wasisolated as a colorless solid. mp 88° C.; Yield, 300 mg, 57%; MS: 318(M+H)⁺; 1H NMR (300 MHz, CDCl₃): δ1.32 (s, 3H), 3.07 (d, J=11 Hz, 1H),3.23 (d, J=11 Hz, 1H), 3.79 (s, 3H), 6.83-7.36 (m, 9H).

EXAMPLE 2 N-Hydroxy-2-(4-methoxy-phenylsulfanyl)-2-phenyl-acetamide

2-(4-Methoxyphenylsulfanyl)-phenylacetic acid ethyl ester was preparedaccording to the general method as outlined in Example 1. Starting fromethyl α-bromophenyl acetate (7.18 g, 31.4 mmol) and 4-methoxythiophenol(4.4 g, 31.4 mmol), 8.5 g of the product was isolated as a light yellowoil. Yield 90%; MS: 303.1 (M+H)⁺.

2-(4Methoxy-phenylsulfanyl)-2-phenyl acetic acid was prepared startingfrom 2-(4-methoxy-phenylsulfanyl)-phenyl-acetic acid ethyl ester (3.0 g,10 mmol) dissolved in methanol (50 ml) and 10 N NaOH (20 ml). Theresulting reaction mixture was worked up as in Example 1. Yield 1.9 g,70%. Low melting solid. MS: 273 (M+H)⁻.

Starting from 2-(4-methoxy-phenylsulfanyl)-phenyl acetic acid (1.05 g,3.83 mmol) and following the procedure as outlined in Example 1, 154 mgof N-hydroxy-2-(4-methoxy-phenylsulfanyl)-2-phenyl-acetamide wasisolated as a colorless solid. mp 155° C.; Yield 14%; MS: 290 (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆): δ3.72 (s, 3H), 4.68 (s, 1H), 6.86-7.44 (m, 9H).

EXAMPLE 3 2-(4-Methoxy-phenylsulfanyl)-2,5-dimethyl-hex-4-enoic acidhydroxyamide

2-(4Methoxy-phenylsulfanyl)-2,5-dimethyl-hex-4-enoic acid ethyl esterwas prepared following the procedure of Example 1, second paragraph.Starting from (4-methoxy-phenylsulfanyl)-propionic acid ethyl ester (3.5g, 14.3 mmol), and isoprenyl bromide (2.25 g, 15 mmol), 2.2 g of theproduct was isolated as an oil. Yield 50%; MS: 310 (M+H)⁺.

2-(4Methoxy-phenylsulfanyl)-2,5-dimethyl-hex-4-enoic acid was preparedstarting from 2-(4-methoxy-phenylsulfanyl)-2,5-dimethyl-hex-4-enoic acidethyl ester (2.0 g, 6.4 mmol) dissolved in methanol (50 ml) and 10 NNaOH (20 ml). The resulting reaction mixture was worked up as outlinedin Example 1. Yield is 1.9 g, 99% of low melting solid. MS: 280 (M+H)⁺.

Starting from 2-(4-methoxy-phenylsulfanyl)-2,5-dimethyl-hex-4-enoic acid(1.67 g, 5.8 mmol) and following the procedure as outlined in Example 1,1.5 g of 2-(4-methoxy-phenylsulfanyl)-2,5-dimethyl-hex-4-enoic acidhydroxyamide was isolated as a colorless solid. mp 89° C.; Yield 94%;MS: 296 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ1.34 (s, 3H), 1.61 (s, 3H),1.74 (s, 3H), 2.41-2.58 (m, 2H), 3.80 (s, 3H), 5.17 (t, J=7.5 Hz, 6.86(d, J=12.4 Hz, 2H), 7.35 (d, J=12.4 Hz, 2H).

EXAMPLE 4 N-Hydroxy-2-(4-methoxy-phenylsulfanyl)-3-methyl-butyramide

2-(4Methoxy-phenylsulfanyl)-3-methyl-butyric acid ethyl ester wasprepared according to the general method of Example 1. Starting fromethyl 2-bromo-3-methyl-butanoate (20.9 g, 100 mmol) and4-methoxybenzenethiol (14.0 g, 100 mmol), 30 g of the product wasisolated. Yield 99%; Light yellow oil; MS: 271 (M+H)⁺.

2-(4Methoxy-phenylsulfanyl)-3-methyl-butyric acid was prepared startingfrom 2-(4-methoxy-phenylsulfanyl)-3-methyl-butyric acid ethyl ester (5.8g, 21.6 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). Theresulting reaction mixture was worked up as outlined in Example 1. Yield5.0 g, 99%. Low melting solid. MS: 242 (M+H)⁺.

Starting from 2-(4-methoxy-phenylsulfanyl)-3-methyl-butyric acid (4.39g, 18.3 mmol) and following the procedure as outlined in Example 1, 1.5g of N-hydroxy-2-(4-methoxy-phenylsulfanyl)-3-methyl-butyramide wasisolated as a colorless solid. mp 119° C.; Yield 33%; MS: 256 (M+H)⁺; ¹HNMR (300, DMSO-d₆): δ0.90-1.07 (m, 6H), 1.84-1.96 (m, 1H), 3.07 (d,J=8.8 Hz, 1H), 3.75 (s, 3H), 6.88 (d, J=15 Hz, 2H), 7.35 (d, J=15 Hz,2H).

EXAMPLE 5N-Hydroxy-2-(4-methoxy-benzenesulfinyl)-2-methyl-3-phenyl-propionamide

N-hydroxy-2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionamide(400 mg, 1.26 mmol) (prepared in Example 1) was dissolved in methanol(100 ml) and 30% H₂O₂ (10 ml) was added. The reaction mixture wasstirred for 48 hours at room temperature at which time it was cooled to0° C. and quenched with saturated Na₂SO₃ (20 ml) solution. The reactionmixture became cloudy. It was stirred for 4 hours before it wasconcentrated in a room temperature water bath, diluted with water,extracted with CHCl₃ and washed with H₂O. The organic layer was driedover MgSO₄, filtered and concentrated. The title compound was isolatedby silica gel column chromatography, eluting with 75%ethylacetate:hexane. Low melting solid. Yield: 220 mg (52%); MS: 334.1(M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ1.11 (s, 2H), 1.22 (s, 3H), 3.84 (s,3H), 7.00-7.61 (m, 9H).

EXAMPLE 6 2-(4Methoxy-benzenesulfinyl)-2,5-dimethyl-hex-4-enoic acidhydroxyamide

Starting from 2-(4-methoxy-benzenesulfanyl)-2,5-dimethyl-hex-4-enoichydroxamide (900 mg, 3.0 mmol) (prepared in Example 3) and following theprocedure outlined in Example 5,2-(4-methoxy-benzenesulfinyl)-2,5-dimethyl-hex-4-enoic acid hydroxyamidewas isolated as a colorless solid. Yield: 104 mg (10%); mp 108° C.; MS:312 (M+H)⁺; ¹H NM (300 MHz, DMSO-d₆): δ0.88 (s, 3H), 1.59 (s, 3H), 1.68(s, 3H), 2.27-2.80 (m, 2H), 5.02 (t, J=7.5 Hz, 1H), 7.09 (d, J=9 Hz,2H), 7.39 (d, J=9 Hz, 2H).

EXAMPLE 7 N-Hydroxy-2-(4-methoxy-benzenesulfinyl)-3-methyl-butyramide

Starting from N-hydroxy-2-(4-methoxy-phenylsulfanyl)-3-methyl-butyramide(1 g, 3.9 mmol) as prepared in Example 4, and following the procedure ofExample 5, N-hydroxy-2-(4-methoxy-benzenesulfinyl)-3-methyl-butyramidewas isolated as a colorless solid. Yield: 420 mg (40%); mp 163° C.; MS;272 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ0.89-1.12 (m, 6H), 1.63-1.74 (m,1H), 3.13 (d, J=7 Hz, 1H), 3.83 (s, 3H), 6.94-7.65 (m, 4H).

EXAMPLE 8 N-Hydroxy-2-(4-methoxy-benzenesulfinyl)-2-phenyl-acetamide

Starting from N-hydroxy-2-(4-methoxy-phenylsulfanyl)-2-phenyl-acetamide(240 mg, 0.83 mmol) as prepared in Example 2, and following theprocedure outlined in Example 5,N-hydroxy-2-(4-methoxy-benzenesulfinyl)-2-phenyl-acetamide was isolatedas colorless solid. Yield: 100 mg (40%); mp 135° C.; MS 304 (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆): δ3.75 (s, 3H), 4.38 (s, 1H), 6.92-7.69 (m, 9H)

EXAMPLE 9 N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionamide

To a stirred solution of 4-methoxybenzenethiol (2.8 gm, 20 mmol) andanhydrous K₂CO₃ (10 gm, excess) in dry acetone (100 ml), α-bromo ethylacetate (3.3 gm, 20 mmol) was added in a round bottom flask and thereaction mixture was heated at reflux for 8 hours with good stirring. Atthe end, the reaction mixture was allowed to cool and the potassiumsalts were filtered off and the reaction mixture was concentrated. Theresidue was extracted with chloroform and washed with H₂O and 0.5 N NaOHsolution. The organic layer was further washed well with water, driedover MgSO₄, filtered and concentrated. (4-methoxy-phenylsulfanyl)-aceticacid ethyl ester was isolated as pale yellow oil. Yield: 4.4 g (100%);MS; 227 (M+H)⁺.

To a stirred solution of 60% 3-chloroperoxybenzoic acid (14.0 gm, 40mmol) in methylene chloride (100 ml) at 0° C.,(4-methoxy-phenylsulfanyl)-acetic acid ethyl ester (4.4 g, 20 mmol) inCH₂Cl₂ (15 ml) was added slowly. The reaction mixture turned cloudy andwas stirred at room temperature for 6 hours. The reaction mixture wasthen diluted with hexanes (300 ml) and stirred for 15 minutes. Thesolids were filtered off and Na₂SO₃ solution was added to the organiclayer which was stirred for at least 3 hours before the mixture wasextracted with CHCl₃ and washed with H₂O. The organic layer was driedover MgSO₄, filtered and concentrated and the colorless(4-methoxy-phenylsulfonyl)-acetic acid ethyl ester was isolated as anoil. Yield: 100%; MS: 259.1 (M+H)⁺.

To stirred solution of the (4-methoxy-benzenesulfonyl)-acetic acid ethylester (2.5 g, 10 mmol), benzyl bromide (1.8 gm,10 mmol) and 18-Crown-6(500 mg) in acetone (250 ml) was added K₂CO₃ (10 gms, excess) and themixture was refluxed for 24 hours At the end, the reaction mixture wasfiltered and the acetone layer was concentrated. The residue obtainedwas extracted with chloroform, washed well with water, dried overanhydrous MgSO₄, filtered and concentrated. The product obtained waspurified by silica-gel column chromatography, eluting with 30% ethylacetate: hexane. The product,2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid ethyl ester wasisolated as a low melting solid. Yield: 3.0 gm 86%; Low melting solid;MS: 349 (M+H)⁺.

To a stirred solution of2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid ethyl ester (348mg, 1 mmol) in methanol (25 ml), 10 N NaOH (10 ml) was added. Thereaction mixture was stirred at room temperature for 48 hours. At theend, the reaction mixture was concentrated and carefully neutralizedwith dilute HCl. The residue obtained was extracted with chloroform,washed well with water, dried and concentrated. The product obtained waspurified by silica-gel column chromatography by eluting with ethylacetate: methanol (95:5) to afford2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid as a colorlessoil. Yield: 250 mg, 89%; MS: 321 (M+H)⁺.

Starting from 2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid (200mg, 0.625 mmol) and following the procedure as outlined in Example 1,150 mg of N-hydroxy-2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionamidewas isolated as a brown solid. Yield: 71%; mp 180° C.; MS: 336 (M+H)⁺;¹H NMR (300 MHz, CDCl₃): δ3.2 (m, 1H), 3.8 (s, 3H), 4.0-4.2 (m, 2H),7.0-8.0 (m, 9H).

EXAMPLE 10 2-(4-Methoxy-benzenesulfonyl)-hexanoic acid hydroxyamide

2-(4Methoxy-phenylsulfanyl)-hexanoic acid ethyl ester was preparedaccording to the general method as outlined in Example 1. Starting fromethyl 2-bromo hexanoate (7 g, 32 mmol) and 4-methoxybenzenethiol (4.2 g,30 mmol), 8.3 g of the product was isolated. Yield 98%; Light yellowoil; MS: 283 (M+H)⁺.

Starting from 2-(4-methoxy-phenylsulfanyl)-hexanoic acid ethyl ester.(2.8 g 10 mmol) and following the procedure as outlined in Example 9, 3g of 2-(4-methoxy-benzenesulfonyl)-hexanoic acid ethyl ester wasisolated as a colorless solid. Yield: 95%; mp 62° C.; MS: 314 (M+H)⁺.

Starting from 2-(4-methoxy-benzenesulfonyl)-hexanoic acid ethyl ester (2g, 6.3 mmol) 1.5 g (83%) of 2-(4-methoxy-benzenesulfonyl)-hexanoic acidwas isolated as a colorless solid by following the procedure as outlinedin Example 9. Mp 116° C.; MS: 287 (M+H)⁺.

Starting from 2-(4-methoxy-benzenesulfonyl)-hexanoic acid (1.0 g, 3.1mmol) and following the procedure as outlined in Example 1, 700 mg of2-(4-methoxy-benzenesulfonyl)-hexanoic acid hydroxyamide was isolated asa colorless solid. Yield: 60%; mp 130° C.; MS: 302 (M+H)⁺; ¹H NMR (300MHz, CDCl₃): δ0.786 (t, J=7.2 Hz, 3H), 1.1-1.3 (m, 4H), 1.6-1.8 (m, 2H),3.7 (m, 1H), 3.9 (s, 3H),7.2 (d, J=11 Hz, 2H), 7.8 (d, J=11 Hz, 2H), 9.3(s, 1H), 10.9 (s, 1H).

EXAMPLE 11 2-(4Methoxy-benzene sulfonyl)-tetradecanoic hydroxyamide

2-(4-Methoxy-phenylsulfanyl)-tetradecanoic acid ethyl ester was preparedaccording to the general method as outlined in Example 1. Starting fromthe corresponding ethyl -2-bromomyristate (5.0 g, 14.9 mmol) and4-methoxythiophenol (1.9 g, 13.4 mmol), 5.0 g of the product wasisolated. Yield 98%; Light yellow oil; MS: 393 (M+H)⁺.

Starting from 2-(4-methoxy-phenylsulfanyl)-tetradecanoic acid ethylester. (3.9 g 10 mmol) and following the procedure as outlined inExample 9, 3.2 g of 2-(4-methoxy-benzenesulfonyl)-tetradecanoic acidethyl ester was isolated as a colorless solid. yield: 76%; Oil; MS: 425(M+H)⁺.

Starting from 2-(4-methoxy-benzenesulfonyl)-tetradecanoic acid ethylester (2.5 g, 5.9 mmol), 2.0 g (85%) of2-(4-methoxy-benzenesulfonyl)-tetradecanoic acid was isolated as acolorless solid by following the procedure as outlined in Example 9. mp82° C.; MS: 397 (M+H)⁺.

Starting from 2-(4-methoxy-benzene sulfonyl)-tetradecanoic acid (1.14 g,2.9 mmol) and following the procedure as outlined in Example 1, 670 mgof 2-(4-methoxy-benzenesulfonyl)-tetradecanoic hydroxyamide was isolatedas an off-white solid. Yield: 57%; mp 114° C.; MS: 414 (M+H)⁺; ¹H NMR(300 MHz, DMSO-d₆): δ0.85 (t, J=7 Hz, 3H), 1.16-1.27 (m, 20H), 1.66 (m,2H), 3.62-3.70 (m, 1H), 3.87 (s, 3H), 7.12 (d, J=15 Hz, 2H), 7.73 (d,J=15 Hz, 2H).

EXAMPLE 12N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-phenyl-propionamide

To a stirred solution of2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid ethyl ester (1.0gm, 3mmol) (example 9), methyl iodide (1 ml, excess) and 18-Crown-6 (500mg) in acetone (250 ml), K₂CO₃ (10 gm, excess) was added and thereaction mixture was refluxed for 24 hours. At the end, the reactionmixture was filtered and the acetone layer was concentrated. The residueobtained was extracted with chloroform, washed well with water, driedover anhydrous MgSO₄, filtered and concentrated. The product obtainedwas purified by silica-gel column chromatography by eluting it with 30%ethyl acetate:hexanes to afford2-(4-methoxy-benzenesulfonyl)-2-methyl-3-phenyl-propionic acid ethylester as a colorless oil. Yield 1.0 g, 98%; MS: 349 (M+H)⁺.

Starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-phenyl-propionicacid ethyl ester (900 mg, 2.7 mmol), 850 mg (quantitative) of2-(4-methoxy-benzenesulfonyl)-2-methyl-3-phenyl-propionic acid wasisolated by following the procedure as outlined in Example 9. Colorlessoil, MS 335 (M+H)⁺.

Starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-phenyl-propionicacid (900 mg, 2.7 mmol) and following the procedure as outlined inExample 1, 450 mg ofN-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-phenyl-propionamidewas isolated as a brown solid. Yield: 48%; mp 58° C.; MS: 350 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃): δ1.4 (s, 3H), 3.1 (d, J=9 Hz, 1H), 3.6 (d, J=9 Hz,1H), 3.9 (s, 3H), 6.8-7.8 (m, 9H).

EXAMPLE 13 2-(4Methoxy-benzenesulfonyl)-2,5-dimethyl-hex-4-enoic acidhydroxyaride

Starting from 2-(4-methoxy-phenylsulfanyl)-propionic acid ethyl ester(Example 1) (12 g; 50 mmol) and following the procedure as outlined inExample 9, 12 g of 2-(4-methoxy-benzenesulfonyl)-propionic acid ethylester was isolated as a semi-solid. yield 100%; MS: 256.1 (M+H)⁺.

Following the procedure as outlined in Example 12,2-(4-methoxy-benzenesulfonyl)-2,5-dimethyl-hex-4-enoic acid ethyl esterwas prepared, starting from (1 g, 3.6 mmol) of2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and isoprenylbromide (1.0 g, 6 mmol). Yield 1.0 g, 81%; Colorless oil; MS: 341(M+H)⁺.

Starting from 2-(4-methoxy-benzenesulfonyl)-2,5-dimethyl-hex-4-enoicacid ethyl ester (900 mg, 2.6 mmol) 800 mg (96%) of2-(4-methoxybenzenesulfonyl)-2,5-dimethyl-hex-4-enoic acid was isolatedas a semi solid by following the procedure as outlined in Example 9. MS:313 (M+H)⁺.

Starting from 2-(4-methoxy-benzenesulfonyl)-2,5-dimethyl-hex-4-enoicacid (1.0 g, 3.2 mmol) and following the procedure as outlined inExample 1, 700 mg of 2-(4-methoxy-benzenesulfonyl)-2,5dimethyl-hex-4-enoic acid hydroxyamide was isolated as a low meltingsolid. Yield: 67%; MS: 328 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ1.3 (s,3H), 1.5 (d, J=6.2 Hz, 6H), 2.5-3.0 (m, 2H), 3.9 (s, 3H), 7.0 (d, J=11Hz, 2H), 7.8 (d, J=11 Hz, 2H).

EXAMPLE 143-(Biphenyl-4-yl)-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamide

Following the procedure as outlined in Example 12,3-(biphenyl-4-yl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acidethyl ester was prepared, starting from (2.7 g,10 mmol) of2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and4-(chloromethyl)biphenyl (2.5 g, 12 mmol). Yield 4.0 g, 91%; Colorlessoil; MS: 438 (M+H)⁺.

Starting from 3-(biphenyl4-yl)-2-(4-methoxy-benzenesulfonyl)-2-methylpropionic acid ethyl ester (3 g, 6.8 mmol), 2.5 g (89%) of3-(biphenyl-4-yl)-2-(4-methoxy-benzenesulfonyl)-2-methyl propionic acidwas isolated as a colorless solid by following the procedure as outlinedin Example 9. mp 161° C.; MS: 411 (M+H)⁺.

Starting from3-(biphenyl-4-yl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acid(2.0 g, 4.8 mmol) and following the procedure as outlined in Example 1,1.2 g of3-(biphenyl4-yl)-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamidewas isolated as colorless solid. Yield: 58%; mp 177° C.; MS: 426 (M+H)⁺;¹H NMR (300 MHz, CDCl₃): δ1.4 (s, 3H), 3.2 (d, J=9 Hz, 1H), 3.7 (d, J=9Hz, 1H), 3.9 (s, 3H), 7.0-7.8 (m, 13H), 9.7 (bs, 1H).

EXAMPLE 152-(4-methoxy-benzenesulfonyl)-2,5,9-trimethyl-deca-4,8-dienoic acidhydroxyamide

Following the procedure as outlined in Example 12,2-(4-methoxy-benzenesulfonyl)-2,5,9-trimethyl-deca-4,8-dienoic acidethyl ester was prepared, starting from (2.7 g, 10 mmol) of2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and geranylbromide (3.0 g, 13 mmol). Yield 4.0 g, 98%; Colorless oil; MS: 409(M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2,5,9-trimethyl-deca-4,8-dienoic acidethyl ester (3 g, 7.4 mmol), 2.8 g (96%) of2-(4-methoxy-benzenesulfonyl)-2,5,9-trimethyl-deca4,8-dienoic acid wasisolated as a colorless oil by following the procedure as outlined inExample 9. MS: 379 (M−H)⁻.

Starting from2-(4-methoxy-benzenesulfonyl)-2,5,9-trimethyl-deca-4,8-dienoic acid (2.0g, 5.2 mmol) and following the procedure as outlined in Example 1, 1.8 gof 2-(4-methoxy-benzenesulfonyl)-2,5,9-trimethyl-deca4,8-dienoic acidhydroxyamide was isolated as a colorless oil. Yield: 88%; MS: 396(M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ1.4 (s, 3H), 1.6 (s, 3H), 1.65 (s,3H), 1.7 (s, 3H), 2.0-3.1 (m,6H), 3.9 (s, 3H), 5.5 (m, 2H), 6.98 (d,J=9.0 Hz, 2H), 7.7 (d, J=9.0 Hz, 2H).

EXAMPLE 163-Cyclohexyl-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamide

Following the procedure as outlined in Example 12,3-cyclohexyl-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acid ethylester was prepared, starting from (2.7 g, 10 mmol) of2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester andbromomethylcyclohexane (1.8 g, 10 mmol). Yield 3.5 g, 95%; Yellow oil;MS: 369 (M+H)⁺.

Starting from 3-cyclohexyl-2-(4-methoxy-benzenesulfonyl)-2-methylpropionic acid ethyl ester (3 g, 8.1 mmol) 2.5 g (90%) of3-cyclohexyl-2-(4-methoxy-benzenesulfonyl)-2-methyl propionic acid wasisolated as colorless solid by following the procedure as outlined inExample 9. mp 116° C.; MS: 341 (M+H)⁺.

Starting from3-cyclohexyl-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acid (2.0g, 5.8 mmol) and following the procedure as outlined in Example 1, 1.1 gof3-cyclohexyl-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamidewas isolated as colorless solid. Yield: 55%; mp 58° C.; MS: 356 (M+H)⁺;¹H NMR (300 MHz, CDCl₃) δ1.4 (s, 3H), 2.3-1.0 (m, 13H), 3.9 (s, 3H), 7.0(d, 8.8 Hz, 2H), 7.69 (d, 9.0 Hz, 2H).

EXAMPLE 7N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[(2-piperidin-1-yl-ethoxy)-phenyl]-propionamide

Following the procedure as outlined in example 12,2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionicacid ethyl ester was prepared, starting from (2.7 g, 10 mmol) of2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and the4-(2-piperidin-1-yl-ethoxy)-benzyl chloride (2.9 g, 10 mmol). Yield 4.8g, 98%; Brown oil; MS: 490 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperdin-1-yl-ethoxy)-phenyl]-propionicacid ethyl ester (4.0 gm, 7.9 mmol) 3.5 g (Yield: 94%) of2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionicacid was isolated is as colorless crystals by following the procedure asoutlined in example 9. Mp 106° C.; MS: 462.5 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionicacid (2.0 g, 4.2 mmol) and following the procedure as outlined inexample 1, 1 g ofN-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionamidewas isolated as colorless solid. Yield: 1 g, 48%; mp 98° C.; MS: 477(M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ1.2 (s, 3H), 3.5-1.5 (m, 16H), 3.9 (s,3H), 4.4 (m, 1H), 6.5-7.8 (m, 8H), 10.8 (bs, 1H).

EXAMPLE 182-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-propionicacid hydroxyamide

Following the procedure as outlined in example 12,2-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-propionicacid ethyl ester was prepared, starting from (2.7 g, 10 mmol) of2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and the1-[2-(4-chloromethyl-phenoxy)ethyl]-azepane (3.03 g, 10 mmol). Yield 4.5g, 90%; Brown oil; MS: 504 (M+H)⁺.

Starting from2-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-propionicacid ethyl ester (4.0 gm, 7.9 mmol) 3.5 g (Yield: 94%) of2-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-propionicacid was isolated as semi-solid by following the procedure as outlinedin example 9. MS: 476 (M+H)⁺.

Starting from2-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-propionicacid (2.0 g, 4.2 mmol) and following the procedure as outlined inexample 1, 1 g of2-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-propionicacid hydroxyamide was isolated as colorless solid. Yield: 1.8 g, 87%; mp68° C.; MS: 491 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ1.23 (s, 3H), 3.5-1.7(m, 18H), 3.8 (s, 3H), 4.2 (m, 1H), 6.4-7.89 (m, 8H), 10.9 (bs, 1H).

EXAMPLE 192-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-pentanoicacid hydroxyamide

2-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-pentanoicacid ethyl ester was prepared according to the general method asoutlined in example 12. Starting from2-(4-methoxy-benzenesulfonyl)-pentanoic acid ethyl ester (3.5 g, 11.7mmol) and 1-[2-(4-chloromethyl-phenoxy)-ethyl]-azepane (3.9 g, 12.8mmol). Yield 2.58 g (42%); brown oil; MS: 532.4 (M+H)⁺.

2-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-pentanoicacid was prepared starting from2-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-pentanoicacid ethyl ester (2 g, 3.76 mmol) dissolved in methanol (300 ml) and 10N NaOH (15 ml). The resulting mixture was worked up as outlined inexample 1. Yield 830 mg (44%); brown solid; mp 55° C.; MS: 504.4 (M+H)⁺.

Starting from2-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-pentanoicacid (690 mg, 1.37 mmol) and following the procedure as outlined inexample 1, 240 mg of2-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-pentanoicacid hydroxyamide was isolated as a yellow solid. Yield 34%; mp 85° C.;MS: 519.2 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ0.71 (t, J=7.3 Hz, 3H),0.78-1.77 (m, 16H), 3.04-3.46 (m, 4H), 3.87 (s, 3H), 4.26 (m, 2H) 6.87(d, J=8.7 Hz, 2H), 7.14 (m, 4H), 7.71 (d, J=9 Hz, 2H), 9.07 (s, 1H), 10(s, 1H).

EXAMPLE 20N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4(2-N,N-diisopropylamino-ethoxy)-phenyl]-propionamide

Following the procedure as outlined in example 12,2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diisopropylamino-ethoxy)-phenyl]-propionic acid ethyl ester was prepared, startingfrom (5.4 g, 20 mmol) of 2-(4-methoxy-benzenesulfonyl)-propionic acidethyl ester and the 4-(2-N,N-diisopropyl amino-ethoxy)-benzyl chloride(6.1 g, 20 mmol). Yield 8.9 g, 88%; Yellow oil; MS: 506.5 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diisopropylamino-ethoxy)-phenyl]-propionic acid ethyl ester (4.0 gm, 7.9 mmol) 3.5g (Yield: 92%) of2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diisopropylamino-ethoxy)-phenyl]-propionic acid was isolated as colorless crystalsby following the procedure as outlined in example 9. Mp 68° C.; MS:478.6 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diisopropylamino-ethoxy)-phenyl]-propionic acid (2.0 g, 4.1 mmol) and following theprocedure as outlined in example 1, 1 g of2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diisopropylamino-ethoxy)-phenyl]-propionamide was isolated as colorless solid.Yield: 1 g, 49%; mp 98° C. (Hcl Salt); MS: 493 (M+H)⁺; ¹H NMR (300 MHz,CDCl₃): δ1.2 (s, 3H), 1.3 (d,6H), 1.4 (d,6H), 3.5-1.5 (m, 6H), 3.9 (s,3H), 4.4 (s, 2H), 6.5-7.8 (m, 8H), 10.8 (bs, 1H).

EXAMPLE 21N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethylamino-ethoxy)-phenyl]-propionamide

Following the procedure as outlined in example 12,2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethylamino-ethoxy)-phenyl]-propionic acid ethyl ester was prepared, startingfrom (5.4 g, 20 mmol) of 2-(4-methoxy-benzenesulfonyl)-propionic acidethyl ester and the 4-(2-N,N-diethyl amino-ethoxy)-benzyl chloride (5.5g, 20 mmol). Yield 8.5 g, 89%; Brown oil; MS: 478.6 (M+H)⁺.

Starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[(2-N,N-diethylamino-ethoxy)-phenyl]-propionic acid ethyl ester (3.5 gm, 7.7 mmol) 3.0g (Yield: 85%) of2-(4-methoxy-benzenesulfonyl)-2-methyl-3′-[(2-N,N-diethylamino-ethoxy)-phenyl]-propionic acid was isolated as colorless crystalsby following the procedure as outlined in example 9. Mp 96-98° C.; MS:450.5 (M+H)⁺.

Starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-ethylamino-ethoxy)-phenyl]-propionic acid (2.0 g, 4.4 mmol) and following theprocedure as outlined in example 1, 1 g of2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N-diethylamino-ethoxy)-phenyl]-propionamide was isolated as colorless solid.Yield: 1 g, 48%; mp 56-59° C. (HCl Salt); MS: 465.5 (M+H)⁺; ¹H NMR (300MHz, CDCl₃): δ1.1 (t, 6H), 1.3 (s,3H), 3.2-3.9 (m, 8H), 3.9 (s, 3H), 4.3(s, 2H), 6.5-7.8 (m, 8H), 10.8 (bs, 1H).

EXAMPLE 22N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-piperidin-1-yl-ethoxy)-phenyl]-propionamide

Following the procedure as outlined in example 12,2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-piperidin-1-yl-ethoxy)-phenyl]-propionicacid ethyl ester was prepared, starting from (5.2 g, 20 mmol) of2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and the3-(2-piperidin-1-yl-ethoxy)-benzyl chloride (6.0 g, 20 mmol). Yield 8.2g, 83%; Brown oil; MS: 490 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-piperidin-1-yl-ethoxy)-phenyl]-propionicacid ethyl ester (6.0 gm, 12.2 mmol) 4.9 g (Yield: 79%) of2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-piperidin-1-yl-ethoxy)-phenyl]-propionicacid was isolated as colorless crystals by following the procedure asoutlined in example 9. Mp 112° C.; MS: 462.5 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-piperidin-1-yl-ethoxy)-phenyl]-propionicacid (3.0 g, 6.5 mmol) and following the procedure as outlined inexample 1, 1.8 g of2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-piperidin-1-yl-ethoxy)-phenyl]propionamidewas isolated as colorless solid. Yield: 1.8 g, 58%; mp 74° C.; MS: 477(M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ1.25 (s, 3H), 1.6-1.8 (m, 6H), 2.5-3.7(m, 8H), 3.9 (s, 3H), 4.4 (t, 2H), 6.7-7.8 (m, 8H), 10.8 (bs, 1H).

EXAMPLE 23 3-(4-{3-[4-(3-Chloro-phenyl)-piperazin-1-yl]-propoxy}-phenyl)-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamide

Following the procedure as outlined in example 12,3-(4-{3-[4-(3-chloro-phenyl)-piperazin-1-yl]-propoxy}-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionicacid ethyl ester was prepared, starting from (2.72 g, 10 mmol) of2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and the1-[2-(4-chloromethyl-phenoxy)-ethyl]-4-(3-chloro-phenyl)-piperazine (4.2g, 11 mmol). Yield 5.5 g, 89%; Brown oil; MS: 616 (M+H)⁺.

Starting from 3-(4-{3-[4-(3-chloro-phenyl)-piperidin-1-yl]-propoxy}-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acid ethylester (4.0 gm, 6.5 mmol) 3.0 g (Yield: 78%) of3-(4-{3-[4-(3-chloro-phenyl)-piperidin-1-yl]-propoxy}-phenyl)-2-(4-methoxy-zenesulfonyl)-2-methyl-propionicacid was isolated as colorless crystals by following the procedure asoutlined in example 9. Mp 196° C.; MS: 588.1 (M+H)⁺.

Starting from 3-(4-{3-[4-(3-chloro-phenyl)-piperidin-1-yl]-propoxy}-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acid (3.0 g,5.1 mmol) and following the procedure as outlined in example 1, 1.8 g of3-(4-{3-[4-(3-chloro-phenyl)-piperidin-1-yl]-propoxy}-phenyl)-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamidewas isolated as pale yellow solid. Yield: 1.8 g, 55%; mp 122° C. (HClSalt); MS: 640 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ1.2 (s, 3H), 3.4-1.5(m, 14H), 3.9 (s, 3H), 4.5 (m, 2H), 6.5-8.2 (m, 12H), 10.3 (bs, 1H).

EXAMPLE 242-(4-Methoxy-benzenesulfonyl)-5-methyl-2-[4-(2-morpholin4-yl-ethoxy)-benzyl]-hex-4-enoicacid hydroxyamide

To a stirred solution of (4-methoxy-benzenesulfonyl)-acetic acid ethylester (5.16 g, 20 mmol), isoprenyl bromide (3.0 g, 20 mmol) and18-Crown-6 (500 mg) in acetone (250 ml) was added K2CO3 (10 gms, excess)and the mixture refluxed foe 24 hours. At the end, the reaction mixturewas filtered and the acetone layer was concentrated. The residueobtained was extracted with chloroform, washed well with water, driedover anhydrous MgSO4, filtered and concentrated. The product obtainedwas purified by silica-gel column chromatography, eluting with 30% ethyacetate: hexane. The product2-(4-methoxy-benzenesulfonyl)-5-methyl-hex-4-enoic acid ethyl ester wasisolated as a colourless oil. Yield: 3.0 g, 93%.

Following the procedure as outlined in example 12,2-(4-Methoxy-benzenesulfonyl)-5-methyl-2-[4-(2-morpholin4-yl-ethoxy)-benzyl]-hex-4-enoicacid ethyl ester was prepared, starting from (3.26 g, 10 mmol) of2-(4-methoxy-benzenesulfonyl)-5-methyl-hex-4-enoic acid ethyl ester and4-(2-morpholin-1-yl-ethoxy)-benzyl chloride (3.0 g, 11 mmol). Yield 4.5g, 82%; Brown oil; MS: 546 (M+H)⁺.

Starting from2-(4-Methoxy-benzenesulfonyl)-5-methyl-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-hex-4-enoicacid ethyl ester (3.0 gm, 5.5 mmol) 2.1 g (Yield: 75%) of2-(4-Methoxy-benzenesulfonyl)-5-methyl-2-[4-(2-morpholin4-yl-ethoxy)-benzyl]-hex-4-enoicacid was isolated as semi-solid by following the procedure as outlinedin example 9. MS: 518.6 (M+H)⁺.

Starting from2-(4-Methoxy-benzenesulfonyl)-5-methyl-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-hex-4-enoicacid (1.0 g, 1.9 mmol) and following the procedure as outlined inexample 1, 450 mg of2-(4-Methoxy-benzenesulfonyl)-5-methyl-2-[4-(2-morpholin4-yl-ethoxy)-benzyl]-hex-4-enoicacid hydroxyamide was isolated as pale yellow solid. Yield: 450 mg, 45%;mp 92° C. (HCl Salt); MS: 570 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ1.3 (d,3H), 1.65 (d, 2H), 3.5-1.8 (m, 14H), 3.9 (s, 3H), 4.5 (m, 2H), 5.4 (m,1H) (m, 8H), 11.5(bs, 1H).

EXAMPLE 25N-Hydroxy-2-(4-ethoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethylamino-ethoxy)-phenyl]-propionamide

To a stirred solution of 4-hydroxy thiophenol (12.6 g, 100 mmol) andtriethyl amine (15.0 g, 150 mmol) in chloroform (400 ml) 2-bromoethylpropionate (18.2 g, 100 mmol) was added drop wise. The reactionmixture was refluxed for 1 hr and cooled to room temperature. Thereaction mixture was washed with water, dried and concentrated.2-(4-hydroxy-phenylsulfanyl)-propionic acid ethyl ester was isolated ascolorless oil. Yield: 22.0 g, 99%, MS: 227 (M+H).

To stirred solution of 2-(4-hydroxy-phenylsulfanyl)-propionic acid ethylester (11.3 g, 50 mmol), and K₂CO₃ (50 g, excess) in acetone (300 ml)ethyl iodide (20 ml, excess) was added and refluxed for 8 hrs. At theend, reaction mixture was filtered and concentrated. The residueobtained was extracted with chloroform and washed well with water. Itwas dried and concentrated. The product,2-(4ethoxy-phenylsulfanyl)-propionic acid ethyl ester was isolated ascolorless oil. Yield: 12.0 g, 98%; MS: 255 (M+H).

2-(4-Ethoxy-phenylsulfanyl)-propionic acid ethyl ester was converted to2-(4-ethoxy-phenylsulfonyl)-propionic acid ethyl ester by following theprocedure as described in example 9, paragraph 2.

Following the procedure as outlined in example 12,2-(4-ethoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethylamino-ethoxy)-phenyl]-propionic acid ethyl ester was prepared, startingfrom (3.5 g, 12.2 mmol) of 2-(4-ethoxy-benzenesulfonyl)-propionic acidethyl ester and the 4-(2-N,N-diethyl amino-ethoxy)-benzyl chloride (3.5g, 12.2 mmol). Yield 4.8 g, 80%; Brown oil; MS: 492.6 (M+H)⁺.

Starting from 2-(4ethoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethylamino-ethoxy)-phenyl]-propionic acid ethyl ester (4.0 gm, 8.1 mmol) 3.2g (Yield: 80%) of2-(4-ethoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethylamino-ethoxy)-phenyl]-propionic acid was isolated as colorlesssemi-solid by following the procedure as outlined in example 9. MS:464.5 (M+H)⁺.

Starting from 2-(4ethoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethylamino-ethoxy)-phenyl]-propionic acid (2.0 g, 4.3 mmol) and following theprocedure as outlined in example 1, 1.2 g of2-(4-ethoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethylamino-ethoxy)-phenyl]-propionamide was isolated as colorless low meltingsolid. Yield: 1.2 g, 57%; (HCl Salt); MS: 478.5 (M+H)⁺; ¹H NMR (300 MHz,CDCl₃): δ0.9 (t, 3H), 1.1 (t, 6H), 1.3 (s,3H), 3.2-3.9 (m, 8H), 3.9 (s,3H), 4.3 (s, 2H), 6.5-7.8 (m, 8H), 10.8 (bs, 1H).

EXAMPLE 26(4E)-2-(4-Methoxy-benzenesulfonyl)-5,9-dimethyl-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-deca-4,8-dienoicacid hydroxyaride

To a stirred solution of (4-methoxy-benzenesulfonyl)-acetic acid ethylester (5.16 g, 20 mmol), geranyl bromide (4.2 g, 20 mmol) and 18-Crown-6(500 mg) in acetone (250 ml) was added K2CO3 (10 gms, excess) and themixture refluxed for 24 hours. At the end, the reaction mixture wasfiltered and the acetone layer was concentrated. The residue obtainedwas extracted with chloroform, washed well with water, dried overanhydrous MgSO₄, filtered and concentrated. The product obtained waspurified by silica-gel column chromatography, eluting with 30% ethyacetate: hexane. The product2-(4-methoxy-benzenesulfonyl)-5,9-dimethyl-deca-4,8-dienoic acid ethylester was isolated as a colourless oil. Yield: 7.0 g 89%.

Following the procedure as outlined in example 12,2-(4-Methoxy-benzenesulfonyl)-5,9-dimethyl-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-deca-4,8-dienoicacid ethyl ester was prepared, starting from (1.0 g, 2.5 mmol) of2-(4-methoxy-benzenesulfonyl)-5,9-dimethyl-deca-4,8-dienoic acid ethylester and 4-(2-morpholin-1-yl-ethoxy)-benzyl chloride (800 mg, 2.5mmol). Yield 1.2 g, 76%; Brown oil; MS: 614 (M+H)⁺.

Starting from2-(4-Methoxy-benzenesulfonyl)-5,9-dimethyl-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-deca-4,8-dienoicacid ethyl ester (2.0 gm, 3.2 mmol) 1.5 g (Yield: 80%) of2-(4-Methoxy-benzenesulfonyl)-5,9-dimethyl-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-deca-4,8-dienoicacid was isolated as semi-solid by following the procedure as outlinedin example 9. MS: 586.6 (M+H)⁺.

Starting from2-(4-Methoxy-benzenesulfonyl)-5,9-dimethyl-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-deca-4,8-dienoicacid (1.0 g, 1.7 mmol) and following the procedure as outlined inexample 1, 550 mg of(4E)-2-(4-Methoxy-benzenesulfonyl)-5,9-dimethyl-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-deca-4,8-dienoicacid hydroxyamide was isolated as pale yellow solid. Yield: 550 mg, 53%;mp 61° C. (HCl Salt); MS: 638 (M+H)⁺.

EXAMPLE 272-[4-(2-Diethylamino-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-hexanoicacid hydroxyamide

2-[4-(2-Diethylamino-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-hexanoicacid ethyl ester was prepared according to the general method asoutlined in example 12. Starting from2-(4-methoxy-benzenesulfonyl)-hexanoic acid ethyl ester (4 g, 12.7 mmol)and [2-(4-chloromethyl-phenoxy)-ethyl]-diethylamine (3.38 g, 14 mmol).Yield 8.21 g crude (100%); brown oil; MS: 520.4 (M+H)⁺.

2-[4-(2-Diethylamino-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-hexanoicacid was prepared starting from2-[4-(2-diethylamino-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-hexanoicacid ethyl ester (8 g, 15.4 mmol) dissolved in methanol (200 ml) and 10N NaOH (30 ml). The resulting mixture was worked up as outlined inexample 1. Yield 3.88 g crude (51%); brown oil; MS: 492 (M+H)⁺.

Starting from2-[4-(2-diethylamino-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-hexanoicacid (3.88 g, 7.89 mmol) and following the procedure as outlined inexample 1, 800 mg of2-[4-(2-diethylamino-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-hexanoicacid hydroxyamide was isolated as a yellow powder. Yield 20%; mp 67° C.;MS: 507.4 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ0.75 (t, J=7.1 Hz, 3H),1.05 (m, 2H), 1.23 (t, J=7.2 Hz, 6H) 1.37-1.91 (m, 2H), 3.13 (m, 4H),3.38-3.51 (m, 4H), 3.87 (s, 3H), 4.3 (t, J=4.8 Hz, 2H), 6.88 (d, J=8.7Hz, 2H), 7.15 (m, 4H), 7.7 (d, J=9 Hz, 2H), 9.07 (s, 1H), 10.1 (s, 1H)

EXAMPLE 28N-Hydroxy-2-(4-n-butoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionamide

Following the procedure as outlined in example 12,2-(4-n-butoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionicacid ethyl ester was prepared, starting from (3.1 g, 10 mmol) of2-(4-n-butoxy-benzenesulfonyl)-propionic acid ethyl ester (Prepared from2-(4-hydroxy-phenylsulfanyl)-propionic acid ethyl ester andn-butylbromide following the procedure outlined in example 27) the4-(2-piperidin-1-yl-ethoxy)-benzyl chloride (3.0 g, 10.1 mmol). Yield4.5 g, 84%; Brown oil; MS: 532.7 (M+H)⁺.

Starting from2-(4-n-butoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionicacid ethyl ester (5.0 gm, 9.4 mmol) 4.2 g (Yield: 88%) of2-(4-n-butoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionicacid was isolated as colorless solid by following the procedure asoutlined in example 9. MS: 504.6 (M+H)⁺.

Starting from2-(4-n-butoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionicacid (3.0 g, 5.9 mmol) and following the procedure as outlined inexample 1, 1.3 g of2-(4-n-butoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidine-1-yl-ethoxy)-phenyl]-propionamidewas isolated as colorless solid. MP. 65 C, Yield: 1.3 g, 42%; (HClSalt); MS: 478.5 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ0.9 (t, 3H), 1.2 (s,3H), 1.3-1.9 (m, 10H), 2.8-4.5 (m, 12H), 6.8-7.8 (m, 8H), 10.8 (bs, 1H).

EXAMPLE 29N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-N,N-diethylamino-ethoxy)-phenyl]-propionamide

Following the procedure as outlined in example 12,2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-N,N-diethylamino-ethoxy)-phenyl]-propionic acid ethyl ester was prepared, startingfrom (5.0 g, 18 mmol) of 2-(4-methoxy-benzenesulfonyl)-propionic acidethyl ester and the 3-(2-N,N-diethyl amino-ethoxy)-benzyl chloride (4.9g, 18 mmol). Yield 8.1 g, 93%; Brown oil; MS: 478.1 (M+H)⁺.

Starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-N,N-diethylamino-ethoxy)-phenyl]-propionic acid ethyl ester (8.1 gm, 16.9 mmol) 6.7g (Yield: 88%) of2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-N,N-diethylamino-ethoxy)-phenyl]-propionic acid was isolated as colorlesssemi-solid by following the procedure as outlined in example 9. MP:78-81; MS: 450.1 (M+H)⁺.

Starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-N,N-diethylamino-ethoxy)-phenyl]-propionic acid (6.7 g, 15 mmol) and following theprocedure as outlined in example 1, 1.5 g of2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-N,N-diethylamino-ethoxy)-phenyl]-propionamide was isolated as colorless low meltingsolid. Yield: 1.5 g, 21%; (HCl Salt); MS: 450.5 (M+H)⁺; ¹H NMR (300 MHz,DMSO-d₆): δ1.21 (t, 6H), 1.26 (s, 3H), 3.18-3.24 (m, 2H), 3.38 (m, 4H),3.43-3.46 (m, 2H), 3.80 (s, 3H), 4.30 (s, 2H), 6.76-6.78 (d, 2H),6.84-7.2 (m, 6H), 10.3 (bs, 1H).

EXAMPLE 30N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-morpholin-1-yl-ethoxy)-phenyl]-propionamide

Following the procedure as outlined in example 12,2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-morpholin-1-yl-ethoxy)-phenyl]-propionicacid ethyl ester was prepared, starting from (5.2 g, 20 mmol) of2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and the3-(2-morpholin-1-yl-ethoxy)-benzyl chloride (6.0 g, 20 mmol). Yield 9.1g, 93%; Brown oil; MS: 492 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-morpholin-1-yl-ethoxy)-phenyl]-propionicacid ethyl ester (10.0 gm, 20.3 mmol) 8.0 g (Yield: 86%) of2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-morpholin-1-yl-ethoxy)-phenyl]-propionicacid was isolated as colorless crystals by following the procedure asoutlined in example 9.; MS: 464.5 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-morpholin-1-yl-ethoxy)-phenyl]-propionicacid (4.55 g, 9.8 mmol) and following the procedure as outlined inexample 1, 440 mg of2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-morpholin-1-yl-ethoxy)-phenyl]-propionamidewas isolated as colorless solid. Yield: 440 mg, 9%; mp 63° C.; MS: 479.5(M+H)⁺; ¹H NMR (300 Mhz, DMSO-d₆): δ1.26 (s, 3H), 3.18-3.8 (m, 12H), 3.9(s, 3H), 4.4 (m, 2H), 6.7-8.8 (m, 8H), 10.8 (bs, 1H).

EXAMPLE 316-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-hexanoicacid hydroxyaride

Following the procedure as outlined in Example 9,6-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-hexanoicacid ethyl ester was prepared, starting from (5.0 g, 20 mmol) of2-(4-methoxy-benzenesulfonyl)-acetic acid ethyl ester and 4-phathalimidobromobutane (5.66 g, 20 mmol). Yield 8.4 g, 97%; Colorless oil; MS: 474(M+H). Starting from6-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-hexanoicacid ethyl ester (8.4 g, 17.7 mmol) 6;95 g (88%) of6-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-hexanoicacid was isolated as colorless oil by following the procedure asoutlined in Example 9. MS: 446 (M−H)⁻.

Starting from6-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-hexanoicacid (4.9 g, 11 mmol) and following the procedure as outlined in Example1, 3.1 g of6-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-hexanoicacid hydroxyamide was isolated as a light brown solid; Yield: 46%; mp146-148° C.; MS: 461.2 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ1.55 (s, 3H),1.61-3.77 (m, 8H), 3.82 (s, 3H), 6.92-8.21 (m, 8H), 10.70 (bs, 1H),11.20 (bs, 1H).

EXAMPLE 323-[4-(2-Diethylamino-ethoxy)-phenyl]-2-(4-furan-2-yl-benzenesulfonyl)-N-hydroxy-2-methyl-propionamide

To a stirred solution of 4-bromo thiophenol (19.0 g, 100 mmol) andtriethyl amine (15.0 g, 150 mmol) in chloroform (400 ml) 2-bromoethylpropionate (18. 2 g, 100 mmol) was added drop wise. The reactionmixture was refluxed for 1 hr and cooled to room temperature. Thereaction mixture was washed with water, dried and concentrated.2-(4-bromo-phenylsulfanyl)-propionic acid ethyl ester was isolated ascolorless oil. Yield: 28.0 g, 99%, MS: 290 (M+H).

2-(4-bromo-phenylsulfanyl)-propionic acid ethyl ester was converted to2-(4-bromo-phenylsulfonyl)-propionic acid ethyl ester by following theprocedure as described in example 9, paragraph 2.

A mixture of 2-(4-bromo-phenylsulfonyl)-propionic acid ethyl ester (6.4g, 20 mmol), 2-(tributyl stannyl)furan (7.5 g, 21 mmol) and (Ph₃P)₄Pd(500 mg) was refluxed in degassed tolune (250 ml) for 8 hrs. At the endreaction mixture was filtered through Celite and concentrated. Theproduct was purified by silica gel column chromatography by eluting itwith 50% ethylacetate:hexane. Colorless oil. Yield: 5.9 g, 95%, MS: 309(M+H).

Following the procedure as outlined in example 12,2-(4-(2-furanyl-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethylamino-ethoxy)-phenyl]-propionic acid ethyl ester was prepared, startingfrom (3.08 g, 10.0 mmol) of 2-(4-(2-furanyl-benzenesulfonyl)-propionicacid ethyl ester and the 4-(2-N,N-diethyl amino-ethoxy)-benzyl chloride(3.5 g, 12.2 mmol). Yield 5.0 g, 97%; Brown oil; MS: 514.6 (M+H)⁺.

Starting from2-(4-(2-furanyl-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethylamino-ethoxy)-phenyl]-propionic acid ethyl ester (5.1 gm, 10.0 mmol) 3.8g (Yield: 78%) of2-(4-(2-furanyl-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethylamino-ethoxy)-phenyl]-propionic acid was isolated as colorless solid byfollowing the procedure as outlined in example 9. MP: 58 C, MS: 486.5(M+H)⁺.

Starting from2-(4-(2-furanyl-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethylamino-ethoxy)-phenyl]-propionic acid (5.0 g, 10.3 mmol) and followingthe procedure as outlined in example 1, 1.2 g of2-(4-ethoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethylamino-ethoxy)-phenyl]-propionamide was isolated as colorless low meltingsolid. Yield: 3.2 g, 62%; (HCl Salt); MS: 502 (M+H)⁺; ¹H NMR (300 MHz,CDCl₃): δ1.23 (t, 6H), 1.4 (s, 2H), 2.8 (q,4H), 3.0 (t, 2H), 4.1 (t,2H), 6.5-8.0 (m, 7H).

EXAMPLE 33N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-butyramide

2-(4-Methoxy-phenylsulfanyl)-butyric acid ethyl ester was preparedaccording to the general method as outlined in example 9. Starting fromethyl 2-bromo butyrate (10.71 g, 55 mmol) and 4-methoxythiophenol (7 g,50 mmol), 5.19 g (40%); clear oil; MS: 255.2 (M+H)⁺.

2-(4Methoxy-benzenesulfonyl)-butyric acid ethyl ester was preparedaccording to the general method as outlined in example 9. Starting from2-(4-methoxy-phenylsulfanyl)-butyric acid ethyl ester (5 g, 20 mmol).Yield 5.74 g (100%); clear oil; MS: 287.1 (M+H)⁺.

Following the procedure as outlined in example 12,2-(4-Methoxy-benzenesulfonyl)-2-[4-(2-morpholin4-yl-ethoxy)-benzyl]-butyricacid ethyl ester was prepared, starting from (3.5 g, 12.2 mmol) of2-(4-methoxy-benzenesulfonyl)-butyric acid ethyl ester and the4-[2-(chloromethyl-phenoxy)-ethyl]-morpholine (2.34 g, 6.7 mmol). Yield5.7 g, 100%; Brown oil; MS: 506.4 (M+H)⁺.

Starting from2-(4-Methoxy-benzenesulfonyl)-2-[4-(2morpholin-4-yl-ethoxy)-benzyl]-butyricacid ethyl ester (5.54 gm, 11 mmol) 2.9 (Yield: 55%) of2-(4-Methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-butyricacid was isolated as colorless semi-solid by following the procedure asoutlined in example 9. MS: 478.3 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-ethoxy)-benzyl]-butyricacid (2.6 g, 5.4 mmol) and following the procedure as outlined inexample 1, 510 mg ofN-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-butyramidewas isolated as a brown solid. Yield 2%; mp 51° C.; MS: 493.3 (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆): δ0.90 (t, J=7.2 Hz, 3H), 1.69-1.96 (m, 4H), 2.67(t, 2H), 3.34 (m, 8H), 3.87 (s, 3H), 4.04 (m, 2H) 6.8 (d, J=8.7 Hz, 2H),7.14 (m, 4H), 7.73 (d, J=4.7 Hz, 2H), 9.08 (s, 1H), 10.8 (s, 1H).

EXAMPLE 34N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-butyramide

Following the procedure as outlined in example 12,2-(4-Methoxy-benzenesulfonyl)-2-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-butyricacid ethyl ester was prepared, starting from (1.0 g, 3.33 mmol) of2-(4-methoxy-benzenesulfonyl)-butyric acid ethyl ester and the1-[2-(4-chloromethyl-phenoxy)-ethyl]-piperidine (0.85 g, 3.36 mmol).Yield 1.07 g, 62%; Brown oil; MS: 504.4 (M+H)⁺.

Starting from 2-(4-Methoxy-benzenesulfonyl)-2-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-butyric acid ethyl ester (3.7 gm, 7.3 mmol) 2.2 g(Yield: 63%) of2-(4-Methoxy-benzenesulfonyl)-2-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-butyricacid was isolated as colorless semi-solid by following the procedure asoutlined in example 9. MS: 476 (M+H)⁺.

Starting from2-(4-Methoxy-benzenesulfonyl)-2-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-butricacid (2.2 g, 4.63 mmol) and following the procedure as outlined inexample 1, 360 mg, ofN-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-butyramidewas isolated as a brown solid. Yield 16%; mp 75° C.; MS: 491.3 (M+H)⁺;¹H NMR (300 MHz, DMSO-d₆): δ0.90 (t, J=7.1 Hz, 3H), 1.36-1.96 (m, 4H),2.4-2.63 (m, 14H), 3.87 (s, 3H), 4.01 (t, J=5.9 Hz, 2H) 6.8 (d, J=8.5Hz, 2H), 7.11 (m, 4H), 7.71 (d, J=8.8 Hz, 2H), 9.09 (s, 1H), 10.8 (s,1H).

EXAMPLE 352-(4-Methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-pentanoicacid hydroxyamide

2-(4-Methoxy-phenylsulfanyl)-pentanoic acid ethyl ester was preparedaccording to the general method as outlined in example 9. Starting fromethyl 2-bromovalerate (8.23 g, 39.3 mmol) and 4-methoxythiophenol (5 g,35.7 mmol), 10.46 g (100%); clear oil; MS: 269 (M+H)⁺.

2-(4-Methoxy-benzenesulfonyl)-pentanoic acid ethyl ester was preparedaccording to the general method as outlined in example 9. Starting from2-(4-methoxy-phenylsulfanyl)-pentanoic acid ethyl ester (6.9 g, 27.4mmol). Yield 7.07 g (86%); clear oil; MS: 300.9 (M+H)⁺.

Following the procedure as outlined in example 12,2-(4-Methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-pentanoicacid ethyl ester was prepared, starting from (3.0 g, 10.8 mmol) of2-(4-methoxy-benzenesulfonyl)-pentanoic acid ethyl ester and the4-[2-(chloromethyl-phenoxy)-ethyl]-morpholine (3.45 g, 11.9 mmol). Yield3.08 g, 62%; Brown oil; MS: 520.4 (M+H)⁺.

Starting from2-(4-Methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-pentanoicacid ethyl ester (2.73 gm, 5.27 mmol) 1.45 g (Yield: 56%) of2-(4-Methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-ethoxy)-benzyl]-pentanoicacid was isolated as colorless semi-solid by following the procedure asoutlined in example 9. MS: 492.3 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-pentanoicacid (1.01 g, 2.05 mmol) and following the procedure as outlined inexample 1, 190 mg of2-(4-methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-ylethoxy)-benzyl]-pentanoicacid hydroxyamide was isolated as a brown solid. Yield 18%; mp 101° C.;MS: 507.4 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ0.71 (t, J=7 Hz, 3H),1.58-1.82 (m, 4H), 3.12-3.98 (m, 12H), 3.87 (s, 3H), 4.35 (t, 2H) 6.89(d, J=8.7 Hz, 2H), 7.15 (m, 4H), 7.74 (d, J=8.9 Hz, 2H), 9.08 (s, 1H).

EXAMPLE 362-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-Methoxy-benzenesulfonyl)-octanoicacid hydroxyamide

2-(4-Methoxy-phenylsulfanyl)-octanoic acid ethyl ester was preparedaccording to the general method as outlined in example 9. Starting fromethyl 2-bromooctanoate (11.8 g, 47.3 mmol) and 4-methoxythiophenol (6 g,43 mmol). Yield: 7.24 g (57%); clear oil; MS: 311.2 (M+H)⁺,2-(4-Methoxy-benzenesulfonyl)-octanoic acid ethyl ester was preparedaccording to the general method as outlined in example 9. Starting from2-(4-methoxy-phenylsulfanyl)-octanoic acid ethyl ester (4.0 g, 13.6mmol). Yield 3.7 g (83%); clear oil; MS: 343.3 (M+H)⁺.

Following the procedure as outlined in example 12,2-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-Methoxy-benzenesulfonyl)-octanoicacid ethyl ester was prepared, starting from (1.69 g, 5.18 mmol) of2-(4-methoxy-benzenesulfonyl)-octanoic acid ethyl ester and the1-[2-(4-chloromethyl-phenoxy)-ethyl]-azepane (1.73 g, 6.0 mmol). Yield4.86 g, 99%; Brown oil; MS: 574.5 (M+H)⁺.

Starting from2-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-Methoxy-benzenesulfonyl)-octanoicacid ethyl ester (4.8 gm, 8.37 mmol) 1.55 g (Yield: 34%) of2-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-Methoxy-benzenesulfonyl)-octanoicacid was isolated as colorless semi-solid by following the procedure asoutlined in example 9. MS: 551 (M+H)⁺.

Starting from2-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-Methoxy-benzenesulfonyl)-octanoicacid (1.09 g, 2.0 mmol) and following the procedure as outlined inexample 1, 300 mg of2-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4Methoxy-benzenesulfonyl)-octanoicacid hydroxyamide was isolated as a yellow solid. Yield 27%; mp 65° C.;MS: 561.6 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ0.81 (t, J=6.6 Hz, 3H),1.08-1.82 (m, 14H), 3.13-3.51 (m, 12H), 3.87 (s, 3H), 4.33 (t, 2H) 6.88(d, J=8.7 Hz, 2H), 7.14 (m, 4H), 7.7 (d, J=9Hz, 2H), 9.06 (s, 1H), 10.28(s, 1H).

EXAMPLE 37 2-(4-Methoxy-benzenesulfanyl)-octanoic acid hydroxyamide

2-(4-Methoxy-phenylsulfanyl)-octanoic acid ethyl ester was preparedaccording to the general method as outlined in example 9. Starting fromethyl 2-bromooctanoate (11.8 g, 47.3 mmol) and 4-methoxythiophenol (6 g,43 mmol). Yield: 7.24 g (57%); clear oil; MS: 311.2 (M+H)⁺.

Starting from 2-(4-Methoxy-benzenesulfanyl)-octanoic acid ethyl ester(3.1 gm, 10 mmol) 2.55 g (Yield: 90%) of2-(4-Methoxy-benzenesulfanyl)-octanoic acid was isolated as colorlesssemi-solid by following the procedure as outlined in example 9. MS: 283(M+H)⁺.

Starting from 2-(4Methoxy-benzenesulfanyl)-octanoic acid (4.25 g, 16mmol) and following the procedure as outlined in example 1, 3.64 g of2-(4-Methoxy-benzenesulfanyl)-octanoic acid hydroxyamide was isolated ascolorless solid. Yield: 76%, MP: 90 C; MS: 298.2 (M+H).

EXAMPLE 38 2-(4-Fluoro-phenylsulfanyl)-octanoic acid hydroxyamide

2-(4-Fluoro-phenylsulfanyl)-octanoic acid ethyl ester was preparedaccording to the general method as outlined in example 9. Starting fromethyl 2-bromooctanoate (6.47 g, 24.7 mmol) and 4-fluorothiophenol (3 g,23.4 mmol). Yield: 6.31 g (90%); clear oil; MS: 299 (M+H)⁺.

Starting from 2-(4-fluoro-benzenesulfanyl)-octanoic acid ethyl ester(3.1 gm, 10 mmol) 2.89 g (Yield: 100%) of2-(4-fluoro-benzenesulfanyl)-octanoic acid was isolated as colorlesssemi-solid by following the procedure as outlined in example 9. MS:268.9 (M+H)⁺.

Starting from 2-(4-fluoro-benzenesulfanyl)-octanoic acid (2.49 g, 9.2mmol) and following the procedure as outlined in example 1, 2.72 g of2-(4-fluoro-benzenesulfanyl)-octanoic acid hydroxyamide was isolated ascolorless solid. Yield: 99%, MP: 58 C; MS: 284(M−H).

EXAMPLE 39 2-(1-methyl-1H-imidazol-2-ylsulfanyl)-octanoic acidhydroxyamide

2-(1-methyl-1H-imidazol-2-ylsulfanyl)octanoic acid ethyl ester wasprepared according to the general method as outlined in example 9.Starting from ethyl 2-bromooctanoate (12.1 g, 48 mmol) and1-methyl-2-mercapto imidazole (5 g, 43.8 mmol). Yield: 12 g (96%); clearoil; MS: 285 (M+H)⁺.

Starting from 2-(1-methyl-1H-imidazol-2-ylsulfanyl)-octanoic acid ethylester (12 gm, 42.2 mmol) 10.2 g (Yield: 95%) of2-(1-methyl-1H-imidazol-2-ylsulfanyl)-octanoic acid was isolated ascolorless solid by following the procedure as outlined in example 9. MP:95 C, MS: 257.1 (M+H)⁺.

Starting from 2-(1-methyl-1H-imidazol-2-ylsulfanyl)-octanoic acid (7.84g 30.6 mmol) and following the procedure as outlined in example 1, 2.77g of 2-(1-methyl-1H-imidazol-2-ylsulfanyl)-octanoic acid hydroxyamidewas isolated as colorless solid. Yield: 33%, MP: 125 C; MS: 272.2 (M+H).

EXAMPLE 40N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-3-naphthalen-2-yl-propionamide

Following the procedure as outlined in Example 9,2-(4-methoxy-benzensulfonyl)-3-naphthalen-2-yl-propionic acid ethylester was prepared, starting from (5.0 g, 20 mmol) of2-(4-methoxy-benzenesulfonyl)-acetic acid ethyl ester and 2-bromomethylnaphthalene (4.4 g, 20 mmol). Yield 7.2 g, 91%; Colorless oil; MS: 399(M+H)⁺.

Starting from 2-(4-methoxy-benzenesulfonyl)-3-naphthalen-2-yl-propionoicacid ethyl ester (3.7 g, 9 mmol) 3.3 g (96%) of2-(4-methoxy-benzenesulfonyl)-3-naphthalen-2-yl-propionoic acid wasisolated as colorless oil by following the procedure as outlined inExample 9. MS: 369.1 (M−H)⁻.

Starting from 2-(4-methoxy-benzenesulfonyl)-3-naphthalen-2-yl-propionicacid (2.2 g, 5.9 mmol) and following the procedure as outlined inExample 1, 820 mg ofN-hydroxy-2-(4-methoxy-benzenesulfonyl)-3-naphthalen-2-yl-propionanidewas isolated as a light brown solid; Yield: 36%; mp 161-163° C.; MS:385.9 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ3.32 (d, J=7.0 Hz, 1H), 3.69 (d,J=7.0 Hz, 1H), 3.82 (s, 3H), 5.02 (s, 1H), 6.92-7.89 (m, 11H).

EXAMPLE 41N-Hydroxy-2-(4-methoxy-phenylmethanesulfonyl)-2-methyl-3-phenylpropionic acid hydroxamide

A mixture of 4-methoxybenzyl mercaptan (7.0 g, 45 mmol), ethyl2-bromopropionate (8.2 g, 46 mmol) and powdered oven dried potassiumcarbonate (10 g, 72 mmol) in 150 mL of acetone was heated at reflux for18 h. The mixture was cooled, filtered, and the filtrate concentrated.The residue was taken up in 150 mL of methylene chloride, washed withwater (150 mL), dried over anhydrous sodium sulfate and evaporated toyield 12 g (99%); colorless liquid; MS 255.1 (M+H). This product is usedwithout further purification.

To an ice cold (5° C.) solution of2-(4-methoxy-phenylmethanesulfanyl)-propionic acid ethyl ester (5.7 g,21 mmol) in 100 mL CH₂Cl₂ was added portionwise (7.2 g, 40 mmol) ofm-chloroperbenzoic acid and the mixture was stirred for 1 h. Thereaction was diluted with hexanes (500 mL) and stirred at 25° C. for 30minute at room temperature. The mixture was filtered and the organiclayer treated with saturated aqueous sodium bisulfite (200 mL). Thehexanes solution containing the product was washed with water, dried(Na₂SO₄) and concentrated. Yield 5.5 g (91%); colorless oil; MS 287.1(M+H)⁺.

Following the procedure as outlined in Example 9,2-(4-Methoxy-phenylmethanesulfonyl)-2-methyl-3-phenyl-propionic acidethyl ester was prepared, starting from2-(4Methoxy-phenylmethanesulfonyl)-propionic acid ethyl ester (2 g, 7mmol) and benzyl bromide (1.3 g, 7.7 mmol). Yield 3.0 g, 100%; Lowmelting solid; MS: 377 (M+H)⁺.

2-(4-Methoxy-phenylmethanesulfonyl)-2-methyl-3-phenyl-propionic acid wasprepared starting from2-(4-Methoxy-phenylmethanesulfonyl)-2-methyl-3-phenyl-propionic acidethyl ester (3.5 g, 9.0 mmol) dissolved in methanol (50 ml) and 10 NNaOH (30 ml). The resulting reaction mixture was worked up as outlinedin Example 9. Yield 930 mg, 31%. Colorless solid, mp: 106-108 C;. MS:347 (M−H)⁺.

Starting from2-(4-Methoxy-phenylmethanesulfonyl)-2-methyl-3-phenyl-propionic acid(2.7 g, 7.0 mmol) and following the procedure as outlined in example 1,266 mg ofN-Hydroxy-2-(4-methoxy-phenylmethanesulfonyl)-2-methyl-3-phenylpropionic acid hydroxamide was isolated as light colorless solid; Yield:10%; mp 58-59° C.; MS: 364.2 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ1.28(s, 3H), 2.84-2.88 (d, 1H), 3.75 (s, 3H), 3.81-3.86 (d, 1H), 4.59-4.63(d, 1H), 4.69-4.74 (d, 1H), 6.94-6.98 (d, 2H), 7.19 (m, 2H), 7.29-7.33(d, 4H), 9.24 (s, 1H), 10.88 (s, 1H).

EXAMPLE 425-Methyl-2-(3-methyl-but-2-enyl)-2-(toluene-4-sulfonyl)-hex-4-enoic acidhydroxyamide

5-Methyl-2-(3-methyl-but-2-enyl)-2-(toluene-4-sulfonyl-hex-4-enoic acidethyl ester was prepared according to general method as outlined inexample 9. Starting from ethyl α-(p-tolylsulfonyl)acetate (2.9 g, 10.9mmol and 4-bromo-2-methyl butene (3.42 g, 23 mmol). Yield 4.6 g; tanoil; MS 379.2 (M+H)⁺.

5-methyl-2-(3-methyl-but-2-enyl)-2-(toluene~sulfonyl)-hex4-enoic acidwas prepared according to general method as outlined in example 9.Starting from5-methyl-2-(3-methyl-but-2-enyl)-2-(toluene~sulfonyl-hex-4-enoic acidethyl ester (4.5g, 11 mmol), ethanol (15 mL) and 10 N sodium hydroxide.

Starting from5-methyl-2-(3-methyl-but-2-enyl)-2-(toluene-4-sulfonyl)-hex-4-enoic acid(4.1 g, 11 mmol) and following the procedure as outlined in example 1,1.07 g of5-Methyl-2-(3-methyl-but-2-enyl)-2-(toluene-4sulfonyl)-hex-4-enoic acidhydroxyamide was isolated as colorless solid; Yield: 30%; mp 108-110°C.; MS: 366.2 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆: δ1.49 (s, 6H), 1.62 (s,6H), 2.41 (s, 3H), 2.53-2.63 (m, 4H), 5.00-5.05 (t, 2H), 7.40-7.43 (d,2H), 7.59-7.62 (d, 2H), 9.04 (s, 1H), 10.80 (s, 1H).

EXAMPLE 43 2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-phenyl-propionicacid hydroxamide

2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-phenyl-propionic acid ethylester (Prepared from 3-mercapto-2-methylfuran) was prepared according tothe general method as outlined in example 9. Starting from2-(2-methyl-furan-3-ylsulfanyl)-propionic acid ethyl ester (2.9 g, 11.9mmol), benzyl bromide (2.22 g, 13 mmol) and potassium carbonate (10 g)in acetone (75 mL). Yield (99%); amber oil; MS 337.1 (M+H)⁺.

2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-phenyl-propionic acid wasprepared according to the general method as outlined in example 9.Starting from 2-(2-methyl-furan-3-ylsulfanyl)-propionic acid ethyl ester(4.8 g, 14.3 mmol), dissolved in ethanol (25 mL and 10 N sodiumhydroxide (10 mL). Yield 3.7 g (84%), white solid, MS 307.4 (M−H).

Starting from 2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-phenyl-propionicacid (3.58 g, 12 mmol) and following the procedure as outlined inexample 1, 1.078 g of2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-phenyl-propionic acidhydroxyamide was isolated as orange color solid; Yield: 29%; mp 68-70°C.; MS: 324 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ1.27 (s, 3H), 2.81-2.86(d, 1H), 3.33 (s, 3H), 3.61-3.66 (d, 1H), 6.66 (s, 1H), 7.19-7.25 (m,5H), 7.76 (s, 1H), 9.09 (s, 1H), 10.81 (s, 1H).

EXAMPLE 442-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionicacid hydroxamide

2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-[4-(2-piperidin-yl-ethoxy)-phenyl]-propionicacid ethyl ester was prepared according to the general method asoutlined in example 9. Starting from2-(2-methyl-furan-3-sulfonyl)-propionic acid ethyl ester (2.4 g, 9.8mmol) and 1-[2-(4-chloromethylphenoxy)-ethyl]-piperidine (2.96 g, 10.7mmol); Yield 2.4 g (92%); amber oil; MS 464.2 (M+H)⁺.

2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionicacid was prepared according to the general method as outlined inexample 1. Starting from2-methyl-2-(2-methyl-furan-3-sulfonyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionicacid ethyl ester (2.01 g, 4.5 mmol), dissolved in ethanol (20 mL) and 10N sodium hydroxide (10 mL). The resulting mixture was worked up asoutline in example 9. Yield 2.03 g; amber crystals mp 66-68° C.; MS 434(M−H).

Starting from2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]propionicacid (2.03 g, 6.0 mmol) and following the procedure as outlined inexample 1, 1.36 g of2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionicacid hydroxyamide was isolated as amber color solid; Yield: 32%; mp115-117° C.; MS: 451.1 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ1.15-1.22 (m,2H), (1.75 (s, 3H), 1.78 (s, 3H) 2.98-3.03 (m, 2H), 3.42-3.47 (m, 2H),3.5 (s, 3H), 6.65 (s, 1H), 6.87-6.90 (d, 2H), 7.12-7.17 (d, 2H), 10.35(s, 1H), 10.60 (s, 1H), 11.70 (s, 1H).

EXAMPLE 452-Methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl-2-(thiophene-2-sulfonyl)-propionicacid hydroxamide

2-Methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl2-(thiophene-2-sulfonyl)-propionicacid ethyl ester was prepared according to the general method asoutlined in example 9. Starting from 2-(thiophene-2-sulfonyl)-propionicacid ethyl ester (prepared from 2-mercaptothiophene and 2-bromopropionicacid ethyl ester) (4.4 g, 17.7 mmol) and1-[2-(4-chloromethylphenoxy)-ethyl]-piperidine (5.3 g, 19.5 mmol); Yield(96%); semi-solid; MS 466.

2-Methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl-2-(thiophene-2-sulfonyl)-propionicacid was prepared according to the general method as outlined in example9. Starting from2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl-2-sulfonyl)-propionicacid ethyl ester (9.8 g, 20 mmol), dissolved in ethanol (20 mL) and 10 Nsodium hydroxide (20 mL). The resulting mixture was worked up as outlinein example 1. Yield 4.5 g (49%); white solid mp 170-172° C.; MS 436.3(M−H).

Starting from2-Methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl-2-(thiophene-2-sulfonyl)-propionicacid (3.6 g, 8.0 mmol) and following the procedure as outlined inexample 1, 345 mg of2-Methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl-2-(thiophene-2-sulfonyl)-propionicacid hydroxyamide was isolated as light colorless solid; Yield: 10%; mp115-118° C.; MS: 451.2 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ1.29 (s, 3H),1.66-1.78 (m, 6H), 2.81-2.86 (d, 1H), 2.96-3.99 (m, 4H), 3.39-3.47 (m,2H), 3.51-3.59 (d, 1H), 4.32 (m, 2H),6.72-6.74 (d 1H), 6.87-6.96 (d,2H), 7.01-7.20 (m, 3H), 7.31-7.33 (m, 1H), 7.69-7.72 (m, 1H), 7.83-7.84(m, 1H), 8.07-8.08 (dd, 1H), 8.17 (dd, 1H), 9.0 (s, 1H) 10.0 (s, 1H),10.78 (s, 1H).

EXAMPLE 462-(octane-1-sulfonyl)-3-[4-(2-piperidin-yl-ethoxy)-phenyl]propionic acidhydroxamide

2-(Octane-1-sulfonyl)-3-[4-(2-piperidin-yl-ethoxy)-phenyl]-propionicacid ethyl ester was prepared according to the general method asoutlined in example 9. Starting from 2-(octane-1-sulfonyl)-propionicacid ethyl ester (5.0 g, 18 mmol) and1-[2-(4chloromethylphenoxy)-ethyl]-piperidine (5.6 g, 19.7 mmol); Yield8.9g (96%); amber oil, MS 495.

2-(Octane-1-sulfonyl)-3-[4-(2-piperidin-yl-ethoxy)-phenyl]-propionicacid was prepared is according to the general method as outlined inexample 9. Starting from2-(octane-1-sulfonyl)-3-[4(2-piperidin-yl-ethoxy)-phenyl]-propionic acidethyl ester (8.9 g, 18 mmol), ethanol (25 mL) and 10 N sodium hydroxide(25 mL). Yield 6.0g (72%).

Starting from2-(Octane-1-sulfonyl)-3-[⁴-(²-piperidin-yl-ethoxy)-phenyl]-propionicacid (3.6 g, 7.7 mmol) and following the procedure as outlined inexample 1, 3.3 g of2-(Octane-1-sulfonyl)-3-[4-(2-piperidin-yl-ethoxy)-phenyl]-propionicacid hydroxyamide was isolated as tan solid; Yield: 89%; mp 69-70° C.;MS: 483.2 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d6): δ0.687 (t, 3H), 1.27-1.69(m, 15H), 2.71-2.75 (d, 1H), 3.51 (s, 3H), 3.65-3.69 (d, 1H), 6.86-6.89(d, 2H), 7.08-7.11 (d, 2H), 9.16 (s, 1H), 10.70 (s, 1H).

EXAMPLE 473-Biphenyl-4-2-methyl-2-(1-methyl-1H-imidazole-2-sulfonyl)-propionicacid hydroxyaride

3-Biphenyl-4-yl-2-methyl-2-(1-methyl-1H-imidazole-2-sulfonyl)-propionicacid ethyl ester was prepared according to the general method asoutlined in example 9. Starting from2-methyl-(1-methyl-1H-imidazolesulfonyl)-propionic acid ethyl esterPrepared from (1-Methyl-2-mercapto imidazole and 2-bromo ethylpropionate) (3.0 g, 12.2 mmol) and 4-chloromethylbiphenyl (2.97 g, 15mmol). Yield 5.0g (99%); low melting solid; MS 413 (M+H)⁺.

3-Biphenyl-4-yl-2-methyl-2-(1-methyl-1H-imidazole-2-sulfonyl)-propionicacid was prepared according to the general method as outlined in example9. Starting from3-biphenyl-4-yl-2-methyl2-(1-methyl-1H-imidazole-2-sulfonyl)-propionicacid ethyl ester (5.0 g, 11.9 mmol), ethanol (15 mL) and 10 N sodiumhydroxide (10 mL). Yield 2.8g (61%); brown solid mp 119-122° C.; MS385.2 (M+H).

Starting from3-Biphenyl4yl-2-methyl-2-(1-methyl-1H-imidazole-2-sulfonyl)-propionicacid (2.8 g, 7.0 mmol) and following the procedure as outlined inexample 1, 112 mg of3-Biphenyl-4-yl-2-methyl-2-(1-methyl-1H-imidazole-2-sulfonyl)-propionicacid hydroxyamide was isolated as tan colored solid; Yield: 4%; mp 112°C.; MS: 399.0 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ0.911 (s, 3H), 3.3 (s,3H), 3.5 (d, 1H), 4.2 (d, 1H), 6.8 (d, 1H), 6.9 (d, 1H), 7.18-7.66 (m,5H), 7.30-7.33 (d, 2H), 7.55-7.58 (d, 2H).

EXAMPLE 48 2-Methyl-3-phenyl-2-(thiophene-2-sulfonyl)-propionic acidhydroxamide

2-Methyl-3-phenyl-2-(thiophene-2-sulfonyl)-propionic acid ethyl esterwas prepared according to the general method as outlined in example 9.Starting from 2-(thiophen-2-sulfonyl)-propionic acid ethyl ester (3.0 g,12 mmol) and benzyl bromide (2.48 g, 15 mmol). Yield 5.2 g (%); tan oil;MS 339.1 (M+H).

2-Methyl-3-phenyl-2-(thiophene-2-sulfonyl)-propionic acid was preparedaccording to the general method as outlined in example 9. Starting from2-methyl-3-phenyl-2-(thiophen-2-sulfonyl)-propionic acid ethyl ester(5.0 g, 15 mmol), ethanol (30 mL) and 10 N sodium hydroxide (10 mL).Yield 5.6g MS 310.0 (M+H).

Starting from 2-Methyl-3-phenyl-2-(thiophene-2-sulfonyl)-propionic acid(5.0 g, 16 mmol) and following the procedure as outlined in example 1,1.8 g of 2-Methyl-3-phenyl-2-(thiophene-2-sulfonyl)-propionic acidhydroxyamide was isolated as colorless solid; Yield: 40%; mp 116-117°C.; MS: 325.9 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ1.29 (s, 3H), 3.33 (d,1H), 3.69 (d 1H), 7.18-7.30 (m, 5H), 7.74 (m, 1H), 8.22 (m, 1H), 9.13(s, 1H), 10.80 (s, 1H).

EXAMPLE 49 2-[8-(1-carboxy-ethanesulfonyl)-octane-1-sulfonyl]-propionicacid hydroxyamide

2-[8-(1-Carboxyl-ethanesulfonyl)-octane-1-sulfonyl]-propionic acid ethylester was prepared according to the general method as outlined inexample 9. Starting from2-[8-(1-ethoxycarbonyl-ethylsulfanyl)-octylsulfanyl]-propionic acidethyl ester (10.2 g, 26 mmol) and sodium peroxymonopersulfate (64 g, 104mmol). Yield 9.87 g (86%); colorless liquid; MS 442.9 (M+H).

2-[8-(1-Carboxy-ethanesulfonyl)-octane-1-sulfonyl]-propionic acid wasprepared according to general method as outline in example 1. Startingfrom 2[8-(1-carboxy-ethanesulfonyl)-octane-1-sulfonyl]-propionic acidethyl ester (3.0 g, 6.8 mmol), ethanol (15 mL) and 10 N sodium hydroxide(15 mL). Yield 2.7 g (98%); white solid mp 99-102° C.; MS 387 (M+NH3)⁺.

Starting from2-[8-(1-Carboxy-ethanesulfonyl)-octane-1-sulfonyl]-propionic acid (2.5g, 6.5 mmol) and following the procedure as outlined in example 1, 641mg of 2-[8-(1-Carboxy-ethanesulfonyl)-octane-1-sulfonyl]-propionic acidhydroxyamide was isolated as amber coloured oil.; Yield: 23%; MS: 434.0(M+NH4)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ1.27-3.23 (m, 22H), 3.33 (m, 2H),8.9 (s, 1H), 9.28 (s, 1H).

EXAMPLE 502-(4-Bromo-benzenesulfonyl)-2-methyl-3-[4-(2-piperidine-1-yl-ethoxy)-phenyl]-propionicacid hydroxamide

2-(4-Bromo-benzenesulfonyl)-2-methyl-3-[4-(2-piperidine-1-yl-ethoxy)-phenyl]-propionicacid ethyl ester was prepared according to general method as outlined inexample 9. Starting from ethyl α-(4-bromophenyl-sulfonyl) acetate (5.0g, 16 mmol) and 1-[2-(4-chloromethylphenoxy)-ethyl]-piperidine (4.97 g,16 mmol). Yield 6.1 g (71%); tan oil; MS 541.1 (M+H)⁺.

2-(4Bromo-benzenesulfonyl)-2-methyl-3-[4-(2-piperidine-1-yl-ethoxy)-phenyl]-propionicacid was prepared according to general method as outlined in example 9.Startingfrom2-(4-bromo-benzenesulfonyl)-2-methyl-3-[4-(2-piperidine-1-yl-ethoxy)-phenyl]-propionicacid ethyl ester (6.5 g, 20 mmol), ethanol (30 ML) and 10 N sodiumhydroxide (15 mL). Yield 6.3 g (100%); yellow solid mp 125-127° C.; MS512.5 (M+H)⁺.

Starting from2-(4Bromo-benzenesulfonyl)-2-methyl-3-[4-(2-piperidine-1-yl-ethoxy)-phenyl]-propionicacid (6.1 g, 612 mmol) and following the procedure as outlined inexample 1, 1.07 g of2-(4-Bromo-benzenesulfonyl)-2-methyl-3-[4-(2-piperidine-1-yl-ethoxy)-phenyl]-propionicacid hydroxyamide was isolated as light yellow solid; Yield: 17%; MS:525.4 (M+H)⁺.

EXAMPLE 513-(4-Bromo-phenyl)-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamide

Following the procedure as outlined in Example 9,3-(4-bromo-phenyl)-2-(4-methoxy-benzensulfonyl)-2-methyl-propionic acidethyl ester was prepared, starting from (3.0 g, 11 mmol)2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and4-bromobenzyl bromide (3.0 g, 12 mmol). Yield 4.67 g, 96%; Colorlessoil; MS: 441 (M+H)⁺.

3-(4-Bromo-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acidwas prepared starting from3-(4-bromo-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acidethyl ester (4.0 g, 9.0 mmol) dissolved in methanol (50 ml) and 10 NNaOH (30 ml). The resulting reaction mixture was worked up as outlinedin Example 9. Yield 3.0 g, 78%. Low melting solid. MS: 413 (M+H)⁺.

Starting from3-(4bromo-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acid(2.7 g, 6.5 mmol) and following the procedure as outlined in example 1,2.26 g of3-(4-bromophenyl)-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamidewas isolated as light colorless solid; Yield: 81%; mp 86-88° C.; MS:429.8 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ1.42 (s,3H), 1.77 (bs, 1H), 3.26(d, J=7.0 Hz, 1H), 3.68 (d, J=7.0 Hz, 1H), 3.85 (s, 3H), 7.01-7.76(m,8H), 9.71-9.88 (bs, 1H).

EXAMPLE 52N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-naphthalen-2-yl-propionamide

Following the procedure as outlined in Example 9,2-(4-methoxy-benzenesulfonyl)-2-methyl-3-naphthalen-2-yl-propionic acidethyl ester was prepared, starting from (5.4 g, 20 mol)2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and2-bromomethyl naphthalene (4.4 g, 20 mmol). Yield 8.0 g, 97%; Colorlesscrystals, mp 182-184° C.; MS: 413 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-methyl-3-naphthalen-2-yl-propionic acidethyl ester (4.6 g, 11 mmol) 4.2 g (98%) of2-(4-methoxy-benzenesulfonyl)-2-methyl-3-naphthalen-2-yl-propionic acidwas isolated as colorless crystals by following the procedure asoutlined in

EXAMPLE 9. mp144-146° C.; MS: 384.9 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-methyl-3-naphthalen-2-yl-propionic acid(2.4 g, 6.2 mmol) and following the procedure as outlined in Example 1,1.6 g ofN-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-naphthalen-2-yl-propionamidewas isolated as a light colorless solid; Yield: 64%; mp 185-187° C.; MS:400.2 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ1.56 (s,3H), 3.28 (d, J=8.0 Hz,1H), 3.81 (d, J=8 Hz,1H), 3.93 (s,3H), 4.88 (bs, 1H), 7.02-7.92 (m,11H).

EXAMPLE 53 N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-3-methyl-butyramide

2-(4Methoxy-phenylsulfanyl)-3-methyl-butyric acid ethyl ester wasprepared according to the general method as outlined in Example 1.Starting from ethyl 2-bromo-3-methyl-butanoate (20.9 g, 100 mmol) and4-methoxybenzenethiol (14.0 g, 100 mmol), 30 g of2-(4-methoxy-phenylsulfanyl)-3-methyl-butyric acid ethyl ester wasisolated. Yield 99%; Light yellow oil; MS: 269 (M+H)⁺.

Starting from 2-(4-methoxy-phenylsulfanyl)-3-methyl-butyric acid ethylester. (2.68 g 10 mmol) and following the procedure as outlined inExample 9 for oxidation, 3 g of2-(4-methoxy-benzenesulfonyl)-3-methyl-butyric acid ethyl ester wasisolated as a colorless solid. yield: 99%; mp 53° C.; MS: 273 (M+H)⁺.

Starting from 2-(4-methoxy-benzenesulfonyl)-3-methyl-butyric acid ethylester (3 g, 10 mmol) 2.7 g (96%) of2-(4-methoxy-benzenesulfonyl)-3-methyl-butyric acid was isolated as acolorless solid by following the procedure as outlined in Example 9. Mp96° C.; MS: 273 (M+H)⁺.

Starting from 2-(4-methoxy-benzenesulfonyl)-3-methyl-butyric acid (2.0g, 7.34 mmol) and following the procedure as outlined in Example 9, 590mg of N-hydroxy-2-(4-methoxy-benzenesulfonyl)-3-methyl-butyramide wasisolated as a colorless solid. Mp 220° C.; Yield 28%; MS: 288 (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆): δ0.88 (d, J=6.7 Hz, 3H), 1.07 (d, J=6.7 Hz, 3H),2.09-2.20 (bs, 1H), 3.53 (d, J=9, 1H), 7.12-7.17 (m, 2H), 7.74-7.79 (m,2H).

EXAMPLE 54 1-(4-Methoxy-benzenesulfonyl)-cyclopentanecarboxylic acidhydroxyamide

Following the procedure as outlined in Example 9,1-(4-methoxy-benzenesulfonyl)-cyclopentanecarboxylic acid ethyl esterwas prepared, starting from (3.0 g, 11.6 mmol) of2-(4-methoxy-benzenesulfonyl)-acetic acid ethyl ester and1,4-dibromobutane (2.4 g, 7.6 mmol). Yield 2.4 g, 78%; Colorless solid,mp 86-88° C.; MS: 313 (M+H)⁺.

1-(4-Methoxy-benzenesulfonyl)-cyclopentanecarboxylic acid was preparedstarting from 1-(4-methoxy-benzenesulfonyl)-cyclopentanecarboxylic acidethyl ester (2.2 g, 7.0 mmol) dissolved in methanol (50 ml) and 10 NNaOH (30 ml). The resulting reaction mixture was worked up as outlinedin Example 9. Yield 1.66 g 83%. Colorless solid; mp 112-115° C.; MS: 285(M+H)⁺.

Starting from 1-(4-methoxy-benzenesulfonyl)-cyclopentanecarboxylic acid(442 mg, 1.5 mmol) and following the procedure as outlined in Example 1,410 mg of 1-(4-methoxy-benzenesulfonyl)cyclopentanecarboxylic acidhydroxyamide was isolated as a colorless solid. mp 89-91° C.; Yield 88%;MS: 300 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ1.65-1.82 (m, 4H), 2.17-2.42(m, 4H), 3.87 (s, 3H), 7.0 (d, J=8Hz, 2H), 7.7 (bs, 1H), 7.72 (d, J=8Hz, 2H), 9.73 (bs, 1H).

EXAMPLE 553-(2-Bromo-phenyl)-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamide

Following the procedure as outlined in Example 9,3-(2-bromo-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acidethyl ester was prepared, starting from (2.0 g, 7.3 mmol) of2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and2-(bromo)benzyl bromide (2.0 g, 8 mmol). Yield 3.1 g, 87%; Colorlessoil; MS: 441 (M+H)⁺.

3-(2-Bromophenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acidwas prepared starting from3-(2-bromo-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acidethyl ester (3.0 g, 68 mmol) dissolved in methanol (50 ml) and 10 N NaOH(30 ml). The resulting reaction mixture was worked up as outlined inExample 9. Yield 1.7 g, 63%. Waxy solid; MS: 414 (M+H)⁺.

Starting from3-(2-bromo-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acid(470 mg, 1.1 mmol) and following the procedure as outlined in Example 9,380 mg of3-(2-bromo-phenyl)-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamidewas isolated as a colorless solid. mp 93-96° C.; Yield 77%; MS: 429(M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ1.3 (s, 3H), 3.32 (d, J=7.0 Hz, 1H),3.69 (d, J=7.0 Hz, 1H), 3.82 (s, 3H), 6.92-7.89 (m, 8H).

EXAMPLE 56 2-(4-methoxy-benzenesulfonyl)-2-methyl-5-phenyl-pent-4-enoicacid hydroxyamide

Following the procedure as outlined in Example 9,2-(4-methoxy-benzenesulfonyl)-2-methyl-5-phenyl-pent-4-enoic acid ethylester was prepared, starting from (3.0 g, 11 mmol)2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and cinnamylbromide (2.1 g, 11 mmol). Yield 3.51 g, 82%; Colorless oil; MS: 389(M+H)⁺.

2-(4Methoxy-benzenesulfonyl)-2-methyl-5-phenyl-pent-4-enoic acid wasprepared starting from2-(4-methoxy-benzenesulfonyl)-2-methyl-5-phenyl-pent-4-enoic acid ethylester (3.0 g, 11 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30ml). The resulting reaction mixture was worked up as outlined in Example9. Yield 1.9 g, 68%; yellowish oil; MS: 361 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-methyl-5-phenyl-pent4-enoic acid (440mg, 1.2 mmol) and following the procedure as outlined in Example 1, 420mg of 2-(4-methoxy-benzenesulfonyl)-2-methyl-5-phenyl-pent-4-enoic acidhydroxyamide was isolated as a colorless solid. mp 162-164° C.; Yield92%; MS: 376 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ1.41 (s, 3H), 3.0-3.16(m, 1H), 3.30 (d, J=11 Hz, 2H), 3.92 (s, 3H), 5.9-6.1 (m, 1H), 6.53 (d,J=11Hz, 1H), 7.1-7.72 (m, 9H), 9.12 (bs,1H).

EXAMPLE 572-(4-methoxy-benzenesulfonyl)-5-phenyl-2-(3-phenyl-propyl)-pentanoicacid hydroxyamide

Following the procedure as outlined in Example 9,2-(4-methoxy-benzenesulfonyl)-5-phenyl-2-(3-phenyl-propyl)-pentanoicacid ethyl ester was prepared, starting from (4.0 g, 15.8 mmol)2-(4-methoxy-benzenesulfonyl)-acetic acid ethyl ester and 3-bromopropylbenzene (6.4 g, 32 mmol). Yield 3.7 g, 47%; Colorless oil; MS: 495(M+H)⁺.

2-(4-Methoxy-benzenesulfonyl)-5-phenyl-2-(3-phenyl-propyl)-pentanoicacid was prepared starting from2-(4-methoxy-benzenesulfonyl)-5-phenyl-2-(3-phenyl-propyl)-pentanoicacid ethyl ester (2.0 g, 4 mmol) dissolved in methanol (50 ml) and 10 NNaOH (30 ml). The resulting reaction mixture was worked up as outlinedin Example 9. Yield 1.18 g, 63%. Waxy solid; MS: 449.2 (M+H−H₂O)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-5-phenyl-2-(3-phenyl-propyl)-pentanoicacid (600 mg, 1.2 mmol) and following the procedure as outlined inExample 1, 420 mg of2-(4-methoxy-benzenesulfonyl)-5-phenyl-2-(3-phenyl-propyl)-pentanoicacid hydroxyaride was isolated as a colorless solid. Mp 118-120° C.;yield 68%; MS: 482 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ1.52-1.68 (m, 2H),1.74-1.92 (m, 2H), 1.98-2.20 (m, 4H), 2.58-2.72 (m,4H), 3.86 (s, 3H),6.93 (d, J=11 Hz, 2H), 7.02-7.63 (m, 10H), 7.81 (d, J=11 Hz, 2H).

EXAMPLE 58 2-allyl-2-(4-methoxy-benzenesulfonyl)-pent-4-enoic acidhydroxyamide

Following the procedure as outlined in Example 9,2-allyl-2-(4-methoxy-benzenesulfonyl)-pent-4-enoic acid ethyl ester wasprepared, starting from (3.0 g, 11.6 mmol)2-(4-methoxy-benzenesulfonyl)-acetic acid ethyl ester and allyl bromide(4 ml, excess). Yield 3.6 g, 92%; Yellow oil; MS: 338 (M+H)⁺.

2-Allyl-2-(4-methoxy-benzenesulfonyl)-pent-4-enoic acid was preparedstarting from 2-allyl-2-4-methoxy-benzenesulfonyl)-pent-4-enoic acidethyl ester (2.2 g, 6.5 mmol) dissolved in methanol (50 ml) and 10 NNaOH (30 ml). The resulting reaction mixture was worked up as outlinedin Example 9. Yield 1.76 g, 87%; yellowish oil; MS: 311 (M+H)⁺.

Stating from 2-allyl-2-(4-methoxy-benzenesulfonyl)-pent4-enoic acid (1.5g, 4.8 mmol) and following the procedure as outlined in Example 1, 1.5 gof 2-allyl-2-(4-methoxy-benzenesulfonyl)-pent4-enoic acid hydroxyamidewas isolated as colorless solid. Mp 114-116 ° C.; Yield 99%; MS: 326(M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ1.62 (s, 1H), 2.70-2.80 (m,4H), 3.9(s, 3H), 5.16-5.27 (m, 4H), 5.81-5.94 (m, 2H), 7.12 (d,J=8 Hz,2H).

EXAMPLE 59 2-(4-methoxy-benzenesulfonyl)-2-propyl-pentanoic acidhydroxyamide

2-alkyl-2-(4-methoxy-benzenesulfonyl)-pent4-enoic acid hydroxyamide (326mg, 1.0 mmol) (example 26) was dissolved in methanol (50 ml) andhydrogenated over 10% Pd/C (100 mg) at room temperature, under 49 psipressure for 4 hours. At the end, the reaction mixture was filtered andmethanol was removed. The resulting solid was crystallized frommethanol. Yield: 250 mg, 75%; MS: 330 (M+H)⁺; ¹H NMR (300 Hz, CDCl₃):δ0.92 (t, J=4.0 Hz, 6H), 1.27-1.59 (m, 4H), 1.78-2.02 (m, 4H), 3.86 (s,3H), 6.04 (bs, 1H), 6.97 (d, J=9 Hz, 2H), 7.76 (d,J=9 Hz, 2H).

EXAMPLE 602-benzyl-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionamide

Following the procedure as outlined in Example 9,2-benzyl-2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid ethylester was prepared, starting from (1.0 g, 3.8 mmol) of2-(4-methoxy-benzenesulfonyl)-acetic acid ethyl ester and benzylbromide(4 ml, excess). Yield 1.2 g, 72%; Yellow oil; MS: 439 (M+H)⁺.

2-Benzyl-2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid wasprepared starting from2-benzyl-2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid ethylester (1.0 g, 2.2 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30ml). The resulting reaction mixture was worked up as outlined in Example9. Yield: 580 mg, 62%; Waxy solid; MS: 409 (M−H)⁻.

Starting from 2-benzyl-2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionicacid (410 mg, 1 mmol) and following the procedure as outlined in Example1, 225 mg of2-benzyl-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionamidewas isolated as a waxy solid. Yield 52%; MS: 426 (M+H)⁺; ¹H NMR (300MHz, CDCl₃): δ3.25 (d, J=14 Hz, 2H), 3.52 (d, J=14 Hz, 2H), 3.9 (s, 3H),6.93 (d, J=8Hz, 2H), 7.02-7.26 (m, 9H), 7.61 (d, 8 Hz, 2H), 7.87 (d,J=4Hz, 1H), 9.58 (bs, 1H).

EXAMPLE 61N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-pyridin-3-yl-propionamide

To a stirred solution of 2-(4-methoxy-benzenesulfonyl)propionic acidethyl ester (2.7 gm, 10 mmol), 3-picolyl chloride hydrochloride (3.2 g,20 mmol). and triethyl benzylammonium chloride (1 g) in methylenechloride (400 ml), 10 N NaOH (30 ml) was added. The reaction wascontinued at room temp for 48 hours. At the end, the organic layer wasseparated and washed well with water. The organic layer was dried,filtered and concentrated. The crude product obtained was purified bysilica-gel column chromatography. The column was eluted with 50% ethylacetate: hexane.2-(4-Methoxy-benzensulfonyl)-2-methyl-3-pyridin-3-yl-propionic acidethyl ester was isolated as brown oil. Yield 3.0 g, 82%; Brown oil; MS:364 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-methyl-3-pyridin-3-yl-propionic acidethyl ester (2.5 g, 6.8 mmol) 1.8 g (79%) of2-(4-methoxy-benzenesulfonyl)-2-methyl-3-pyridin-3-yl-propionic acid wasisolated as a colorless solid by following the procedure as outlined inExample 9. mp 58° C.; MS: 336 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-methyl-3-pyridin-3-yl-propionic acid(410 mg, 1 mmol) and following the procedure as outlined in Example 1,225 mg ofN-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-pyridin-3-yl-propionamidewas isolated as a colorless solid. Yield 52%; mp 98° C.; MS: 351 (M+H)⁺;¹H NMR (300 MHz, CDCl₃): δ1.4 (s, 3H), 3.1 (d, J=9.0, 1H), 3.65 (d,J=9.1, 1H), 3.9 (s, 3H), 7-8.5 (m, 8H).

EXAMPLE 62 2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-decanoicacid hydroxyamide

Starting from 2-(4-methoxy-benzenesulfonyl)-acetic acid ethyl ester (7.5g, 29 mmol) and 1-bromooctane (6.7 g, 35 mmol) 8 g of the mono octylatedcompound 2-(4-methoxy-benzenesulfonyl)-decanoic acid ethyl ester wasisolated by following the procedure outlined in Example 9. Yield: 8.0 g74%; MS: 370 (M+H)⁺.

Following the procedure as outlined in example 29,2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-decanoic acid ethylester was prepared, starting from (8.0 g, 21.6 mmol) of2-(4-methoxy-benzenesulfonyl)-decanoic acid ethyl ester and 3-picolylchloride hydrochloride (4.1 g, 25 mmol). Yield 6.5 g, 68%; Brown oil;MS: 462 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-decanoic acid ethylester (5.0 g, 11 mmol), 4.5g (91%) of2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-decanoic acid wasisolated as a colorless solid by following the procedure as outlined inExample 9. Mp 159° C.; MS: 434 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-decanoic acid (2.5 g,5.7 mmol) and following the procedure as outlined in Example 1, 1.4 g of2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-decanoic acidhydroxyamide was isolated as colorless solid. Yield: 50%; mp 62° C.; MS:448 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ0.86 (t, 6.9 Hz, 3H), 1.25-2.17(m, 14H), 3.3 (d, J=14 Hz, 1H), 3.5 (d, J=14 Hz, 1H), 3.9 (s, 3H),6.8-8.6 (m, 8H).

EXAMPLE 632-(4Methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hex-4-enoicacid hydroxyamide

Following the procedure as outlined in Example 9,2-(4-methoxy-benzenesulfonyl)-5-methyl-hex-4-enoic acid ethyl ester wasprepared, starting from (6.0 g, 23 mmol)2-(4-methoxy-benzenesulfonyl)-acetic acid ethyl ester and isoprenylbromide (3.0 g, 20 mmol). Yield 6.52 g, 86%; Colorless oil; MS: 327(M+H)⁺.

Following the procedure as outlined in Example 29,2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hex-4-enoicacid ethyl ester was prepared, starting from (4.0 g, 12.2 mmol) of2-(4-methoxy-benzenesulfonyl)-5-methyl-hex-4-enoic acid ethyl ester and3-picolylchloride hydrochloride (2.1 g, 13 mmol). Yield 4.14 g, 81%;Brown oil; MS: 418 (M+H)⁺.

2-(4Methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hex-4 enoicacid was prepared starting from2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hex-4-enoicacid ethyl ester (4.0 g, 9.5 mmol) dissolved in methanol (50 ml) and 10N NaOH (30 ml). The resulting reaction mixture was worked up as outlinedin Example 9. Yield 3.2 g, 87%; ivory solid; mp 117-119° C.; MS: 390(M+H)⁺. Starting from2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hex-4-enoicacid (2.1 g, 5.4 mmol) and following the procedure as outlined inExample 1, 1.82 g of2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hex-4-enoicacid hydroxyamide was isolated as a colorless solid. Yield: 82%; mp89-92° C.; MS: 405 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ1.63 (s, 3H), 1.76(s, 3H), 2.62-2.78 (m, 2H), 3.3 (d, J=4.0 Hz, 1H), 3.63 (d, J=4.0 Hz,1H), 3.82 (s, 3H), 5.26 (m, 1H), 7.12-7.88 (m, 6H), 8.27-8.33 (m. 2H).

EXAMPLE 64

2-Benzyl-4-diisopropylamino-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-butyraminde

Following the procedure as outlined in Example 29,2-benzyl4-diisopropylamino-2-(4-methoxy-benzenesulfonyl)-butyric acidethyl ester was prepared, starting from (3.0 g, 8.5 mmol) of2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid ethyl ester(Example 9) and 2-diisopropylaminoethyl chloride hydrochloride (4.0 g,20 mmol). Yield 3.2 g, 79%; Ivory solid, mp 89-91° C.; MS: 476.4 (M+H)+.

Starting from2-benzyl-4-diisopropylamino-2-(4-methoxy-benzenesulfonyl)-butyric acidethyl ester (3.53 gm, 7.5 mmol) 2.8 g (86%) of2-benzyl-4-diisopropylamino-2-(4-methoxy-benzenesulfonyl)-butyric acidwas isolated as colorless crystals by following the procedure asoutlined in Example 9. Mp 136-138° C.; MS: 448.5 (M+H)+.

Starting from2-benzyl-4-diisopropylamino-2-(4-methoxy-benzenesulfonyl)-butyric acid(1.85 g, 4.1 mmol) and following the procedure as outlined in Example 1,1.3 g of2-benzyl-4-diisopropylamino-N-hydroxy-2-(4-methoxy-benzenesulfonyl)butyramidewas isolated as a low melting, waxy solid; Yield: 68%; MS: 463.3 (M+H)+;1H NMR (300 MHz, CDCl₃): δ0.98 (d, J=11 Hz, 6H), 1.16 (d, J=11 Hz, 6H),1.92 (m, 2H), 2.46 (m, 2H), 2.71 (m, 2H), 3.18 (m, 1H), 3.48 (m, 1H),3.86 (s, 3H), 6.98 (d, J=8 Hz, 2H), 7.18-7.22 (m, 5H), 7.92 (d, J=8 Hz,2H), 8.12 (s, 1H).

EXAMPLE 653cyclohexyl-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-propionamide

Following the procedure as outlined in Example 9, 3-cyclohexyl-2-(z,methoxy. benzenesulfonyl)-propionic acid ethyl ester was prepared,starting from (4.0 (m, 15 mmol) 2-(4-methoxy-benzenesulfonyl)-aceticacid ethyl ester and 1-bromomethyl cyclohexane (2.7 g, 15 mmol). Yield5.0 g, 94%; Colorless oil; MS: 355 (M+H)⁺.

Following the procedure as outlined in Example 29,3-cyclohexyl-2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-propionicacid ethyl ester was prepared, starting from3-cyclohexyl-2-(4-methoxy-benzenesulfonyl)-propionic acid ethylester(1.5 g, 4.2 mmol) and 3-picolyl chloride (1.0 g, 6 mmol). Yield 1.0g, 38%; Colorless oil; MS 446 (M+H)⁺.

Starting from3-cyclohexy-2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-yl-methyl-propionicacid ethyl ester (1.3 g, 2.9 mmol) 1.0 g (83%) of3-cyclohexyl-2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-propionicacid was isolated as colorless crystals by following the procedure asoutlined in Example 9. Mp 92° C.; Ms: 417.5 (M+H)⁺Starting from3methoxy-benzenesulfonyl)-2pyridin-3-ylmethyl proponic acid (1.0 g, 2.4mol) and following the procedure as outlined in Example 1, 80 mg of3-cyclohexyl-N-hydroxy-2-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-propionamidewas isolated as a colorless hydrochloride salt; Yield: 71%; mp 57-60°C.; MS: 433 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ0.8-2.08 (m, 13H), 3.3 (d,J=14 Hz, 1H), 3.7 (d, J=14 Hz, 1H), 3.9 (s, 3H), 7.0-8.5 (m, 8H).

EXAMPLE 662-(4-Methoxy-benzenesulfonyl)4-methyl-2-pyridin-3-ylmethyl-pentanoicacid hydroxyamide

Following the procedure as outlined in Example 9,2-(4-methoxy-benzenesulfonyl)-4-methyl-pentanoic acid ethyl ester wasprepared, starting from (5.0 g, 20 mmol)2-(4-methoxy-benzenesulfonyl)-acetic acid ethyl ester and1-bromo-2-methyl propane (2.6 g, 20 mmol). Yield 6.0 g, 95%; Colorlessoil; MS: 315 (M+H)⁺.

Following the procedure as outlined in Example 29,2-(4-methoxy-benzenesulfonyl)4-methyl-2-pyridin-3-ylmethyl-penanoic acidethyl ester was prepared, starting from (3.1 g, 10 mmol) of2-[(4-methoxy-benzenesulfonyl)4-methyl pentanoic acid ethyl ester and3-picolyl chloride hydrochloride (1.8 g, 11 mmol). Yield 3.0 g, 75%;Colorless oil; MS: 406 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)4-methyl-2-pyridin-3-ylmethyl-pentanoicacid ethyl ester (1.2 g, 2.9 mmol) 1.0 g (91%) of2-(4-methoxy-benzenesulfonyl)-4-methyl-2-pyridin-3-ylmethyl-pentanoicacid was isolated as colorless crystals by following the procedure asoutlined in Example 9. Mp 188-186° C.; MS: 378 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-4-methyl-2-pyridin-3-ylmethyl-pentanoicacid (800 mg, 2.1 mmol) and following the procedure as outlined inExample 1, 180 mg of2-(4-methoxy-benzenesulfonyl)4-methyl-2-pyridin-3-ylmethyl-pentanoicacid hydroxyamide was isolated as a colorless solid; Yield: 21%; mp 78°C.; MS: 393.4 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ0.65 (d, 6.3 Hz, 3H),0.89 (d, J=6.2 Hz, 3H), 1.7 (m, 1H), 2.06 (m, 2H), 3.85 (s, 3H), 6.8-8.5(m, 10H).

EXAMPLE 67N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-quinolin-6-yl-propionamide

Following the procedure as outlined in Example 29,2-(4-methoxy-benzenesulfonyl)-2-methyl-3-quinolin-6-yl-propionic acidethyl ester was prepared, starting from (5.2 g, 20 mmol) of2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and7-bromomethyl quinoline (4.4 g, 20 mmol). Yield 4.5 g, 54%; Pale yellowsolid; mp 86° C.; MS: 414 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-methyl-3-quinolin-6yl-propionic acidethyl ester (3.0 gm, 7.2 mmol) 2.5g (90%) of2-(4-methoxy-benzenesulfonyl)-2-methyl-3-quinolin-6-yl-propionic acidwas isolated as colorless crystals by following the procedure asoutlined in Example 9. mp 106-108° C.; MS: 386.4 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-methyl-3-quinolin-6-yl-propionic acid(2.0 gm, 5.2 mmol) and following the procedure as outlined in Example 1,1.2 g ofN-hydroxy-2-(methoxy-benzenesulfonyl)-2-methyl-3-quinolin-6-yl-propionamidewas isolated as a colorless solid; Yield: 57%; mp 206° C.; MS: 401.4(M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ1.4 (s, 3H), 3.19 (m, 1H), 3.8-4.0 (m,4H), 7.1-8.95 (m, 12H).

EXAMPLE 682-(4Methoxy-benzenesulfonyl)-6-phenoxy-2-pyridin-3-ylmethyl-hexanoicacid hydroxyamide

Following the procedure as outlined in Example 9,2-(4-methoxy-benzenesulfonyl)-6-phenoxy-hexanoic acid ethyl ester wasprepared, starting from (2.5 g, 10 mmol)2-(4-methoxy-benzenesulfonyl)-acetic acid ethyl ester and1-bromo-4-phenoxy butane (2.2, 10 mmol). Yield 3.8 g, 93%; Colorlessoil; MS: 407 (M+H)⁺.

Following the procedure as outlined in Example 9,2-(4-methoxy-benzenesulfonyl)-6-phenoxy-2-pyridin-3-ylmethyl-hexanoicacid ethyl ester was prepared, starting from (3.1 g, 10 mmol)2-(4-methoxy-benzenesulfonyl)-6-phenoxy-hexanoic acid ethyl ester and3-picolyl chloride (1.8 g, 11 mmol). Yield 3.5 g, 71%; Colorless oil;MS: 498 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-6-phenoxy-2-pyridin-3-ylmethyl-hexanoicacid ethyl ester (3.0 g, 6.0 mmol), 2.8g (Yield: Quantitative) of2-(4-methoxy-benzenesulfonyl)-6-phenoxy-2-pyridin-3-ylmethyl-hexanoicacid was isolated as colorless crystals by following the procedure asoutlined in Example 9. Mp 148-151° C.; MS: 470.5 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-6-phenoxy-2-pyridin-3-ylmethyl-hexanoicacid (2.0 g, 4.3 mmol) and following the procedure as outlined inExample 1, 1.5 g of2-(4-methoxy-benzenesulfonyl)-6-phenoxy-2-pyridin-3-ylmethyl-hexanoicacid hydroxyamide was isolated as a colorless solid; Yield: 72%; mp 68°C.; MS: 485.5 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ1.5-2.5 (m, 8H), 3.4(bs, 2H), 3.8 (s, 3H), 6.8-8.7 (m, 13H).

EXAMPLE 692-(4Methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hexanoic acidhydroxyamide

Following the procedure as outlined in Example 9,2-(4-methoxy-benzenesulfonyl)-5-hexanoic acid ethyl ester was prepared,starting from (10.0 g, 39 mmol) 2-(4-methoxy-benzenesulfonyl)-aceticacid ethyl ester and 1-bromo-3-methyl butane (6.0 g, 40 mmol). Yield 8.5g, 62%; Colorless oil; MS: 329 (M+H)⁺.

Following the procedure as outlined in Example 9,2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hexanoicacid ethyl ester was prepared, starting from (6.0 g, 18 mmol) of2-(4-methoxy-benzenesulfonyl)-5-methyl-hexanoic acid ethyl ester andpicolyl chloride hydrochloride (4.1 g, 25 mmol). Yield 4.5 g, 60%; Brownoil; MS: 420 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hexanoicacid ethyl ester (3.0 g, 7.1 mmol) 2.6 g (92%) of2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hexanoicacid was isolated as a colorless solid by following the procedure asoutlined in Example 9. Mp: 173 C.; MS: 392 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hexanoicacid (1.0 g, 2.5 mmol) and following the procedure as outlined inExample 1, 800 mg, of2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hexanoicacid hydroxyamide was isolated as a colorless solid; The hydrochloridewas prepared by passing hydrogen chloride gas through methanol solutionof the hydroxyamide. Yield: 72%; mp 62° C. (HCl salt); MS: 408 (M+H)⁺;¹H NMR (300 MHz, CDCl₃): δ0.76 (m, 6H), 1.2-2.0 (m, 5H), 3.5 (bq, 2H),7.1-8.8 (m, 8H), 11.1 (bs,1H).

EXAMPLE 70 2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-hexanoicacid hydroxyamide

(4Methoxy-phenylsulfanyl)-acetic acid tert-butyl ester was preparedaccording to the general method as outlined in Example 1. Starting fromthe corresponding 1-bromo tert-butyl acetate (5.3 g, 27 mmol) and4-methoxybenzenethiol (3.7 g, 27 mmol), 6.4 g of the product wasisolated. Yield 98%; Light yellow oil; MS: 255 (M+H)⁺.

2-(4-Methoxy-benzenesulfonyl)-acetic acid tert-butyl ester was preparedaccording to the general method as outlined in Example 9. Starting from2-(4-methoxy-benzenesulfanyl)-acetic acid tert-butyl ester (5.0 g, 20mmol) and 3-chloroperoxybenzoic acid 57% (12.0 g, 40 mmol), 5.3 g of theproduct was isolated. Yield 92%; Waxy solid; MS: 287.1 (M+H)⁺.

2-(4-Methoxy-benzenesulfonyl)-pyridin-3-ylpropionic acid tert-butylester was prepared 10 according to the procedure as outlined in Example9. Starting from 2-(4-methoxy-benzenesulfonyl)acetic acid tert-butylester (20.0 g, 70.0 mmol) and 3-picolyl chloride (7.28 g, 44.4 mmol),10.5 g of the product was isolated by silica gel chromatography (50%ethyl acetate: hexane). Yield 63%; white solid; mp 93-94° C.; MS: 378.0(M+H)⁺.

2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-hexanoic acidtert-butyl ester was prepared according to the procedure as outlined inExample 9. Starting from2-(4-methoxy-benzenesulfonyl)-pyridin-3-ylpropionic acid tert-butylester (2.0 g, 5.3 mmol) and n-butyl bromide (0.73 g, 5.3 mmol), 1.20 gof the product isolated. Yield 52%; yellowish gum; MS: 434.3 (M+H)⁺.

A mixture of the2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-hexanoic acidtert-butyl ester (1.1 g, 2.5 =mol), in methylene chloride/ TFA (I: 1)wasstirred at room temperature for about 2 hours. The solvents were thenevaporated and the2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-hexanoic acid waspurified by silica gel chromatography (30% methanol/methylene chloride).Yield 0.90 g, 94%; white solid; mp 70° C.; MS: 376.1 (M−H)⁻.

2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-hexanoic acidhydroxyamide was prepared according to the method as outlined inExample 1. Starting from2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-hexanoic acid (0.31g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.13 gof the product isolated. Yield 37%; pale yellowish solid; mp 65° C.; MS:392.9 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ0.80 (t, J=7.2 Hz, 3H),1.10-1.25 (m, 2H), 1.25-1.50 (m, 2H), 1.70-2.00 (m, 2H), 3.53 (d, J=14.4Hz, 1H), 3.62 (d, J=14.4 Hz, 1H), 3.88 (s, 3H), 7.15 (d, J=8.9 Hz, 2H),7.71 (d, J=8.9 Hz, 2H), 7.90-8.00 (m, 1H), 8.40-8.45 (m, 1H), 8.70-8.85(m, 2H), 11.0 (brs, 1H); IR (KBr, cm⁻¹): 3064m, 2958s, 2871m, 1671m.

EXAMPLE 71 2-(4-methoxy-benzenesulfonyl)-2-oct-2-ynyl-dec-4-ynoic acidhydroxyamide.

The title compound was prepared according to the procedure as outlinedin example 9. Starting from 2-(4-methoxy-benzenesulfonyl)-acetic acidtert-butyl ester (2.86 g, 10 mmol) and 1-bromo-2-octyne (3.80 g, 20mmol), 4.4 g of the product isolated. Yield 100%; yellowish gum; MS:446.9 (M+H)⁺.

2-(4-Methoxy-benzenesulfonyl)-2-oct-2-ynyl-dec-4-ynoic acid was preparedaccording to the method as outlined in example 70. Starting from2-(4-methoxy-benzenesulfonyl)-2-oct-2-ynyl-dec-4-ynoic acid tert-butylester (4.40 g, 10.0 mmol), 2.0 g of the product isolated. Yield 49%;white solid; mp 61° C.; MS: 345.1 (M−H)⁻.

2-(4-Methoxy-benzenesulfonyl)-2-oct-2-ynyl-dec4-ynoic acid hydroxyamidewas prepared according to the method as outlined in example 1. Startingfrom 2-(4-methoxy-benzenesulfonyl)-2-oct-2-ynyl-dec-4-ynoic acid (0.36g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.25 gof the product isolated. Yield 62%; white solid; mp 83-84° C.; 462.0(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ0.82-0.90 (m, 6H), 1.15-1.45 (m,12H), 1.90-2.05 (m, 4H), 2.86 (brd, J=17.0 Hz, 2H), 3.00 (brd, J=17.0Hz, 2H), 3.87 (s, 3H), 7.15 (d, J=10.0 Hz, 1H), 7.71 (d, J=10.0 Hz, 1H),9.20 (brs, 1H), 10.90 (brs, 1H); IR (KBr, cm⁻¹): 3344s, 3208m, 2930m,2870m, 1677s, 1592s;

Anal. Calc'd for C₂₅H₃₅NO₅S: C, 65.05; H, 7.64; N. 3.03. Found: C,65.26; H, 7.68; N, 2.90.

EXAMPLE 72 2-(4-Methoxy-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acidhydroxyamide

2-(4-Methoxy-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid tert-butylester was prepared according to the procedure as outlined in Example 9.Starting from 2-(4-methoxy-benzenesulfonyl)-acetic acid tert-butyl ester(2.86 g, 10 mmol) and 1-bromo-2-butyne (2.68 g, 20 mmol), 3.50 g of theproduct was isolated. Yield 90%; white solid; mp 85-87° C.; MS: 391.0(M+H)⁺.

2-(4Methoxy-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid was preparedaccording to the procedure as outlined in example 70. Starting from2-(4-methoxy-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid tert-butylester (3.0 g, 7.7 mmol), 2.5 g of the product isolated. Yield 97%; whitesolid; mp 141-143° C.; MS: 333.1 (M−H)⁻.

2-(4-Methoxy-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid hydroxyamidewas prepared according to the method as outlined in example 1. Startingfrom 2-(4-methoxy-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid (0.27g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.23 gof the product was isolated. Yield 89%; white solid; mp 135-137° C.; MS:349.9 (M+H)⁺1 ; ¹H NMR (300 MHz, DMSO-d₆) δ1.67 (s, 6H), 2.70-3.10 (m,4H), 3.88 (s, 3H), 7.15 (d, J=10.0 Hz, 2H), 7.71 (d, J=10.0 Hz, 2H),9.20 (brs, 1H), 10.90 (brs, 1H); IR (KBr, cm−1): 3301s, 3161m, 2922m,1640m, 1595s, 1500m.

EXAMPLE 73 2-(4-Methoxy-benzenesulfonyl)-2-prop-2-ynyl-pent-4-ynoic acidhydroxyamide

2-(4-Methoxy-benzenesulfonyl)-2-prop-2-ynyl-pent-4-ynoic acid tert-butylester was prepared according to the procedure as outlined in Example 9.Starting from 2-(4-methoxy-benzenesulfonyl)-acetic acid tert-butyl ester(2.0 g, 7.0 mmol) and propargyl bromide (1.77 g, 15 mmol), 1.90 g of theproduct was isolated. Yield 75%; white solid; mp 113-115° C.; MS: 362.1(M+H)⁺.

2-(4-Methoxy-benzenesulfonyl)-2-prop-2-ynyl-pent-4-ynoic acid wasprepared according to the procedure as outlined in Example 70. Startingfrom 2-(4-methoxy-benzenesulfonyl)-2-prop-2-ynyl-pent-4-ynoic acidtert-butyl ester (1.70 g, 4.7 mmol), 1.30 g of the product isolated.Yield 90%; white solid; mp 156° C.; MS: 305.1 (M−H)⁻.

2-(4-Methoxy-benzenesulfonyl)-2-prop-2-ynyl-pent-4-ynoic acidhydroxyamide was prepared according to the method as outlined inExample 1. Starting from(4-methoxy-benzenesulfonyl)-2-prop-2-ynyl-pent-4-ynoic acid (0.25 g,0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.22 g ofthe product was isolated. Yield 85%; white solid; mp 156° C.; MS: 321.9(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ2.00-2.13 (m, 2H), 3.00-3.30 (m, 4H),3.90(s, 3H), 7.01 (d, J=9.0 Hz, 2H), 7.82 (d, J=9.0 Hz, 2H), 8.76 (brs,1H), 10.65 (brs, 1H); IR (KBr, cm−1): 3392s, 3293s, 3271m, 2955m, 1650s,1594s;

Anal. Calc'd for C₁₅H₁₅NO₅S: C, 56.07; H, 4.70; N, 4.36. Found: C,55.65; H, 4.67; N, 4.10.

EXAMPLE 742-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec-4-ynoic acidhydroxyamide

The title compound was prepared according to the procedure as outlinedin Example 38. Starting from2-(4-methoxy-benzenesulfonyl)-pyridin-3-ylpropionic acid tert-butylester (2.20 g, 5.8 mmol) and 1-bromo-2-octyne (1.14 g, 6 mmol), 2.60 gmof the product isolated. Yield 92%; yellowish gum; MS: 486.0 (M+H)⁺.

A mixture of the2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec-4-ynoic acidtert-butyl ester (2.60 g, 5.35 mmol), in methylene chloride/TFA (1:1) isstirred at room temperature for about 2 hours. (Ref. example 70) Thesolvents are then evaporated and the2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec-1-ynoic acid waspurified by silica gel chromatography (˜30% methanol/methylenechloride). Yield: 2.0 g, 87%; White solid; mp 146° C.; MS: 428.1 (M−H)⁻.

2-(4Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec-4-ynoic acidhydroxyamide was prepared according to the procedure outlined inExample 1. Starting from2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec-4-ynoic acid(0.71 g, 1.62 mmol) and hydroxylamine hydrochloride (1.39 g, 20 mmol),0.48 g of the product was isolated. Yield 67%; off-white solid; mp 65°C.; MS: 445.0 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ0.84 (t, J=6.8 Hz, 3H),1.10-1.40 (m, 6H), 1.85-2.00 (m, 2H), 2.79 (d, J=17.9 Hz, 1H), 2.90 (d,J=17.9 Hz, 1H), 3.50 (d, J=13.7 Hz, 1H), 3.74 (d, J=13.7 Hz, 1H), 3.89(s, 3H), 7.19 (d, J=9.0 Hz, 2H), 7.76 (d, J=9.0 Hz, 2H), 7.85-7.89 (m,1H), 8.37-8.40 (m, 1H), 8.70-8.80 (m, 2H), 11.0 (brs, 1H); IR (KBr,cm−1): 3157m, 3095m, 2954s, 2932s, 2858m, 1671m, 1593s;

Anal. Calc'd for C₂₃H₂₈N₂O₅S.HCl.0.9H₂O: C, 55.56; H, 6.24; N, 5.63.Found: C, 55.84; H, 6.19; N, 5.59.

EXAMPLE 752-(4Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-pent-4-ynoic acidhydroxyamide

2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-pent-4-ynoic acidtert-butyl ester was prepared according to the procedure as outlined inExample 38. Starting from2-(4-methoxy-benzenesulfonyl)-pyridin-3-ylpropionic acid tert-butylester (3.77 g, 10 mmol) and propargyl bromide (1.74 g, 13 mmol), 2.50 gof the product was isolated. Yield 60%; yellowish solid; mp 132-133° C.;MS: 416.0 (M+H)⁺.

2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-pent-4-ynoic acid wasprepared according to the procedure as outlined in Example 70. Startingfrom 2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-pent-4-ynoicacid tert-butyl ester (2.0 g,4.8 mmol), 1.2 g of the product isolated.Yield 69%; white solid; mp 119-121° C.; MS: 358.1 (M−H)⁻.

2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-pent-4-ynoic acidhydroxyamide was prepared according to the method as outlined inExample 1. Starting from2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-pent-4-ynoic acid(0.29 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 m, 10 mmol),0.065 g of the product was isolated. Yield 25%; off-white solid; mp 70°C.; MS: 375.0 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ1.19 (brs, 1H),2.90-3.00 (m, 2H), 3.55 (d, J=13.8 Hz, 1H), 3.67 (d, J=13.8 Hz, 1H),3.89 (s, 3H), 7.18 (d, J=9.0 Hz, 2H), 7.75 (d, J=9.0 Hz, 2H), 7.80-7.89(m, 1H), 8.35-8.40 (m, 1H), 8.70-8.80 (m, 2H), 11.1 (brs, 1H); IR (KBr,cm−1): 3168m, 3095s, 1670m, 1593s.

EXAMPLE 76 2-(4-Fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-hex-4-ynoicacid hydroxyamide

2-(4-Fluoro-benzenesulfanyl)-acetic acid tert-butyl ester was preparedaccording to the procedure as outlined in Example 1. Starting from4-fluorothiophenol (30.0 g, 230 mmol) and tert-butyl bromoacetate (45.67g, 230 mmol), 53.4 g of the product was isolated. Yield 100%; paleyellowish oil; MS: 243.1 (M+H)⁺.

2-(4-Fluoro-benzenesulfonyl)-acetic acid tert-butyl ester was preparedaccording to the general method as outlined in Example 9. Starting from2-(4-fluoro-benzenesulfanyl)-acetic acid tert-butyl ester (48.4 g, 200mmol) and 3-chloroperoxybenzoic acid (121.3g (57%), 400 mmol), 48.0 g ofthe product was isolated. Yield 88%; pale yellowish oil; MS: 275.1(M+H)⁺.

The title compound was prepared according to the procedure as outlinedin Example 70. Starting from2-(4-fluoro-benzenesulfonyl)-3-pyridin-3-ylpropionic acid tert-butylester (1.83 g, 5.0 mmol) and 1-bromo-2-butyne (0.67 g, 5.0 mmol), 2.18 gof the product was isolated. Yield 100%; yellowish gum; MS: 419.2(M+H)⁺.

2-(4-Fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-hex-4-ynoic acid wasprepared according to the method as outlined in Example 38. Startingfrom 2-(4-fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-hex-4-ynoic acidtert-butyl ester (2.1 g, 5.0 mmol), 1.20 g of the product was isolated.Yield 67%; off-white solid; mp 150° C.; MS: 360.2 (M−H)⁻.

2-(4-Fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl- hex-4-ynoic acidhydroxyamide was prepared according to the method as outlined inExample 1. Starting from2-(4-fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-hex-4-ynoic acid (0.29g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.15 gof the product was isolated. Yield 45%; white solid; mp 190° C.; MS:377.2 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ1.60 (s, 3H), 2.70-3.00 (m,2H), 3.53 (d, J=13.8 Hz, 1H), 3.74 (d, J=13.8 Hz, 1H), 7.50-7.58 (m,2H), 7.80-7.95 (m, 3H), 8.35-8.40(m, 1H), 8.74-8.79 (m, 2H), 11.1 (brs,1H); IR (KBr, cm−1): 3154m, 3105s, 3068s, 2875m, 1696s, 1630w, 1590s;

Anal. Calc'd for C₁₈H₁₇FN₂O₄S.HCl. 0.5H₂O: C, 51.24; H, 4.54; N, 6.64.Found: C, 51.21; H, 4.35; N, 6.46.

EXAMPLE 77 2-(4-Fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec-4-ynoicacid hydroxyamide

The title compound was prepared according to the procedure as outlinedin Example 9. Starting from2-(4-fluoro-benzenesulfonyl)-3-pyridin-3-ylpropionic acid tert-butylester (1.83 g, 5.0 mmol) and 1-bromo-2-octyne (0.95 g, 5.0 mmol), 1.80 gof the product was isolated. Yield 56%; yellowish gum; MS: 474.3 (M+H)⁺.

2-(4-Fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec-4-ynoic acid wasprepared according to the method as outlined in Example 70. Startingfrom 2-(4-fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec4-ynoic acidtert-butyl ester (1.80 g, 3.8 mmol), 1.40 g of the product was isolated.Yield 88%; off-white solid; mp 123-124° C.; MS: 416.3 (M−H)⁻.

2-(4Fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec-1-ynoic acidhydroxyamide was prepared according to the method as outlined inExample 1. Starting from2-(4-fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec-4-ynoic acid (0.67g, 1.62 mmol) and hydroxylamine hydrochloride (1.39 g, 20 mmol), 0.22 gof the product was isolated. Yield 29%; white solid; mp 180-182° C.; MS:433.2 (M+H)⁺; ¹H NMR (300 M, DMSO-d₆) δ0.84 (t, J=6.8 Hz, 3H), 1.20-1.40(m, 6H), 1.90-2.05 (m, 2H), 2.75 (d, J=19.9 Hz, 1H), 2.94 (d, J=19.9 Hz,1H), 3.54 (d, J=13.7 Hz, 1H), 3.75 (d, J=13.7 Hz, 1H), 7.40-7.60(m, 2H),7.70-8.00 (m, 3H), 8.30-8.40 (m, 1H), 8.70-8.80 (m, 2H), 11.1 (brs, 1H),IR (KBr, cm−1): 3154m, 3105s, 3067m, 2957s, 2933s, 2873m, 1690s, 1631m.

Anal. Calc'd for C₂2H₂₅FN₂O₄S.HCl: C, 56.34; H, 5.59; N, 5.97. Found: C,56.18; H, 5.54; N,5.76.

EXAMPLE 78 2-(4-Fluoro-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acidhydroxyamide

2-(4-Fluoro-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid tert-butylester was prepared according to the procedure as outlined in Example 9.Starting from 2-(4-fluoro-benzenesulfonyl)-acetic acid tert-butyl ester(4.87 g, 20 mmol) and 1-bromo-2-butyne (5.36 g, 40 mmol), 6.0 g of theproduct was isolated. Yield 77%; white solid; mp 85° C.; MS: 379.1(M+H)⁺.

2-(4-Fluoro-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid was preparedaccording to the procedure as outlined in Example 70, starting from2-(4-fluoro-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid tert-butylester (3.50 g, 8.47 mmol), 2.35 g of the product was isolated. Yield79%; white solid; mp 129-131° C.; MS: 642.8 (2M−H)⁻.

2-(4Fluoro-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid hydroxyamidewas prepared according to the method as outlined in Example 1. Startingfrom 2-(4-fluoro-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid (0.26 g,0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.21 g ofthe product was isolated. Yield 77%; white solid; mp 161-163° C.;MS:338.1(M+H)+; ¹H NMR (300 MHz, DMSO-d₆) 5 1.67(s, 6H), 2.80-3.10 (m,4H), 7.51 (dd, J=9.0, 9.0 Hz, 2H), 7.87 (m, 2H), 9.26 (brs, 1H), 10.95(brs, 1H); IR (KBr, cm−1): 3336s, 3245m, 1681s, 1589m, 1493m;

Anal. Calc'd for C₁₆H16FNO₄S: C, 56.96; H, 4.78; N, 4.15. Found: C,56.59; H, 4.75; N, 4.04.

EXAMPLE 792-(4Methoxy-benzenesulfonyl)-5-methyl-2-(3-methyl-but-2-enyl)-hex-4-enoicacid hydroxyamide

Following the procedure as outlined in Example 9,2-(4-methoxy-benzenesulfonyl)-5methyl-2-(3-methyl-but-2-enyl)-hex-4-enoicacid ethyl ester was prepared, starting from (5.0 g, 20 mmol)2-(4-methoxy-benzenesulfonyl)-acetic acid ethyl ester and isoprenylbromide (6.0 g, 40 mmol). Yield 7.0 g, 88%; Colorless oil; MS: 395(M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-5-methyl-2-(3-methyl-but-2-enyl)-hex-4-enoicacid ethyl ester (3.5 g, 9 mmol), 3.3g (97%) of2-(4-methoxy-benzenesulfonyl)-5-methyl-2-(3-methyl-but-2-enyl)-hex-4-enoicacid was isolated as a colorless oil by following the procedure asoutlined in Example 9. MS: 365 (M−H)⁻.

Starting from2-(4-methoxy-benzenesulfonyl)-5-methyl-2-(3-methyl-but-2-enyl)-hex-4-enoicacid (2.6 g, 7.0 mmol) and following the procedure as outlined inExample 1, 1.36 g of2-(4-methoxy-benzenesulfonyl)-5-methyl-2-(3-methyl-but-2-enyl)-hex-4-enoicacid hydroxyamide was isolated as a colorless solid. Yield: 67%; mp93-96° C.; MS: 383 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ1.68 (s, 6H), 1.73(s, 6H), 2.72 (m, 4H), 3.82 (s, 3H), 5.12 (m, 2H), 6.92 (d, J=8 Hz, 2H),7.33 (bs, 1H), 7.72 (d, J=8 Hz, 2H), 9.71 (bs, 1H).

EXAMPLE 80 2-(4-methoxy-phenylsulfanyl)-heptanoic acid hydroxyamide.

2-(4-Methoxy-phenylsulfanyl)-heptanoic acid ethyl ester (13.8 g, 98%)was prepared according to the general method as outlined in example 1starting from ethyl 2bromoheptanoate (11 g, 47 mmol) and4-methoxythiophenol (6 g, 42.8 mmol), as a yellow oil; MS: 297.2 (M+H)⁺.

2-(4-Methoxy-phenylsulfanyl)-heptanoic acid was prepared starting with2-(4-methoxy-phenylsulfanyl)-heptanoic acid ethyl ester (4 g, 13.5 mmol)dissolved in methanol (300 ml) and 10 N NaOH (25 ml). The resultingreaction mixture was worked up as outlined in example 1. Yield 3 g(83%). yellow oil. MS: 267.1 (M−H)⁻.

Starting from 2-(4-methoxy-phenylsulfanyl)-heptanoic acid (2.49 g, 9.32mmol) and following the procedure as outlined in example 1, 1.83 g of2-4-(methoxy-phenylsulfanyl)-heptanoic acid hydroxyamide was isolated asan off white solid. Mp 90-95° C.; Yield 70%; MS: 284.0 (M+H)⁺; ¹H NMR(300 MHz, DMSO-d₆): δ0.826 (t, J=6.9 Hz, 3H), 1.135-1.76 (m, 8H), 3.35(m, 1H), 3.82 (s, 3H), 6.91-7.49 (m, 4H).

EXAMPLE 81 (49A) 2R*-(4-methoxy-phenyl-S*-sulfinyl)-heptanoic acidhydroxyamide and (49B) 2S*-(4-methoxy-phenyl-R*-sulfinyl)-heptanoic acidhydroxyamide

Starting from 2-(4-methoxy-phenylsulfanyl)-heptanoic acid hydroxyamide(1.69 g, 6 mmol) and following the procedure outlined in example 5, thetwo diastereomers of 2-(4-methoxy-phenylsulfinyl)-heptanoic acidhydroxyamide were separated on a silica gel column using 75% ethylacetate:hexanes. The less polar isomer,2R*-(4-methoxy-phenyl-S*-sulfinyl)-heptanoic acid hydroxyamide wasisolated as a white powder. Yield: 390 mg (22%); mp 115° C.; MS: 300.0(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): 0.828 (t, J=6.2 Hz, 3H), 1.18-1.23(m, 6H), 1.73-1.99 (m, 2H), 3.11-3.15 (m, 1H), 3.82 (s, 3H), 7.09-7.61(m, 4H). The more polar isomer,2S*-(4-methoxy-phenyl-R*-sulfinyl)-heptanoic acid hydroxyamide wasisolated as a gray solid. Yield: 200 mg (11%); mp 112° C.; MS: 300.0(M+H)⁺, ¹H NMR (300 MHz, DMSO-d₆): δ0.754 (t, J=6.9 Hz, 3H), 1.014-1.121(m, 6H), 1.58-1.89 (m, 2H), 3.10-3.15 (m, 1H), 3.834 (s, 3H), 7.13-7.65(m, 4H).

EXAMPLE 822-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-morpholinlyl-ethoxy)-phenyl]-propionichydroxyamide hydrochloride

Following the procedure as outlined in example 12,2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-morpholin-1-ylethoxy)-phenyl]-propionicacid ethyl ester was prepared, starting from (4.0 g, 15 mmol) of2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and4-(morpholin-1-yl-ethoxy)-benzyl chloride hydrochloride (2.9 g, 10mmol). Yield 4.8 g, 98%; Brown oil; MS: 492 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-morpholin-1-yl-ethoxy)-phenyl]-propionicacid ethyl ester (4.0 gm, 8.1 mmol) 3.2 g (Yield: 84%) of2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-morpholin-1-yl-ethoxy)-phenyl]-propionicacid was isolated as colorless crystals by following the procedure asoutlined in example 9. Mp 171° C.; MS: 464 (M+H)⁺.

Starting from2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-morpholin-1-yl-ethoxy)-phenyl]-propionicacid (4.0 g, 8.6 mmol) and following the procedure as outlined inexample 1, 2.5 g of2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-morpholin-1-yl-ethoxy)-phenyl]-propionichydroxyamide was isolated as colorless solid. The hydrochloride salt wasprepared by reacting the free base with methanolic hydrogen chloride at0° C. Yield: 2.5 g, 60%; mp 98° C.; MS: 479 (M+H)⁺; ¹H NMR (300 MHz,CDCl₃): 1.36 (s, 3H), 3.8-12.6 (m, 16H), 3.9 (s, 3H), 4.1-4.3 (m, ¹H),6.6 (d, J=8 Hz, 2H), 6.96 (d, J=9 Hz, 2H), 7.1 (d, 8 Hz, 2H), 7.84 (d, 9Hz, 2H), 10.8 (bs, 1H).

EXAMPLE 831-Benzyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic Acidhydroxyamide

To a stirred solution of 4-methoxybenzenethiol (2.8 gm, 20 mmol) andanhydrous K₂CO₃ (10 gm, excess) in dry acetone (100 ml), α-bromo ethylacetate (3.3 gm, 20 mmol) was added in a round bottom flask and thereaction mixture was heated at reflux for 8 hours with good stirring. Atthe end, the reaction mixture was allowed to cool and the potassiumsalts were filtered off and the reaction mixture was concentrated. Theresidue was extracted with chloroform and washed with H₂O and 0.5 N NaOHsolution. The organic layer was further washed well with water, driedover MgSO₄, filtered and concentrated. (4-methoxy-phenylsulfanyl)-aceticacid ethyl ester was isolated as pale yellow oil. Yield: 4.4 g (100%);

MS; 227 (M+H)⁺. To a stirred solution of 60% 3-chloroperoxybenzoic acid(14.0 gm, 40 mmol) in methylene chloride (100 ml) at 0° C.,(4-methoxy-phenylsulfanyl)-acetic acid ethyl ester (4.4 g, 20 mmol) inCH₂Cl₂ (15 ml) was added slowly. The reaction mixture turned cloudy andwas stirred at room temperature for 6 hours. The reaction mixture wasthen diluted with hexanes (300 ml) and stirred for 15 minutes. Thesolids were filtered off and Na₂SO₃ solution was added to the organiclayer which was stirred for at least 3 hours before the mixture wasextracted with CHCl₃ and washed with H₂O. The organic layer was driedover MgSO4, filtered and concentrated and the colorless(4-methoxy-phenylsulfonyl)-acetic acid ethyl ester was isolated as anoil. Yield: 100%; MS: 259.1 (M+H)⁺.

To a stirred solution of diethanol amine (10.5 g, 100 mmol), andanhydrous K₂CO₃ (30 gm, excess) in dry acetone (250 ml), benzyl bromide(17.2 gm, 100 mmol) was added in a round bottom flask and the reactionmixture was heated at reflux for 8 hours with good stirring. At the end,the reaction mixture was allowed to cool and the potassium salts werefiltered off and the reaction mixture was concentrated. The residue wasextracted with chloroform and washed with H₂O. The organic layer wasfurther washed well with water, dried over McSO₄, filtered andconcentrated. Colorless oil. Yield: 19.0 g, 97%; MS: 196 (M+H).

N-Benzyldiethanolamine (9.75 g, 50 mmol) was dissolved in saturatedmethanolic hydrochloric acid and concentrated to dryness. Thehydrochloride thus formed was dissolved in methylene chloride (300 ml)and thionyl chloride (20 g, excess) was added dropwise and stirred atroom temperature for 1 hr. At the end reaction mixture was concentratedto dryness and the product bis-(2-chloro-ethyl)-benzyl aminehydrochloride was used for further transformation with out anypurification. Yield: 13.0 g, 97%; Mp: MS: 232 (M+H).

To a stirred solution of bis-(2-chloro-ethyl)-benzyl amine hydrochloride(6.6 g, 24.7 mmol), 18-Crown-6 (500 mg), and anhydrous K₂CO₃ (30 gm,excess) in dry acetone (250 ml), (4-methoxy-phenylsulfonyl)-acetic acidethyl ester (6.12 gm, 24 mmol) was added in a round bottom flask and thereaction mixture was heated at reflux for 16 hours with good stirring.At the end, the reaction mixture was allowed to cool and the potassiumsalts were filtered off and the reaction mixture was concentrated. Theresidue was extracted with chloroform and washed with H₂O. The organiclayer was further washed well with water, dried over MaSO₄, filtered andconcentrated. The dark brown reaction mixture was purified by silica gelcolumn chromatography by eluting it with 30% ethylacetate:hexane and theproduct 4-(4-Methoxy-benzensulfonyl)-1-benzyl-piperidine-4-carboxylicacid ethyl ester was isolated as Brown oil. Yield: 6.0 g, 60%; MS: 418(M+H).

4-(4-Methoxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acidethyl ester (5.0 g, 11.9 mmol) was dissolved in MeOH/THF (1:1, 200 ml)and stirred at room temperature for 72 hrs. At the end reaction mixturewas concentrated and the product was neutralized with con. Hcl bydissolving it in water (200 ml). After the neutralization reactionmixture was concentrated to dryness. Ice cold water (100 ml) was addedto the solid and filtered. The product4-(4-Methoxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acid wasdried at 50 C. and taken to next step with out any purification.Colorless solid. Yield: 3.2 g, 69% ; MS: 390 (M+H).

To a stirred solution of4-(4-Methoxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acid (2.0g, 5.1 mmol) and DMF (2 drops) in CH₂Cl₂ (100 ml) at 0° C., oxalylchloride (1.0 gm, 8 mmol) was added in a drop-wise manner. After theaddition, the reaction mixture was stirred at room temperature for 1hour. Simultaneously, in a separate flask a mixture of hydroxylaminehydrochloride (2.0 gm, 29 mmol) and triethylamine (5 ml, excess) wasstirred in THF:water (5:1, 30 ml) at 0° C. for 1 hour. At the end of 1hour, the oxalyl chloride reaction mixture was concentrated and the paleyellow residue was dissolved in 10 ml of CH₂Cl₂ and added slowly to thehydroxylamine at 0° C. The reaction mixture was stirred at roomtemperature for 24 hours and concentrated. The residue obtained wasextracted with chloroform and washed well with water. The productobtained was purified by silica gel column chromatography and elutedwith chloroform the product4-(4-Methoxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acidhydroxyamide was isolated as a colorless solid. mp 90-95° C.; Yield, 1.2g, 48%; MS: 405 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ2.29 (m, 3H),2.76-2.79 (m, 2H), 3.43 (m 4H),4.30 (s, 2H), 7.14-7.17 (d,2H), 7.50-7.73(m, 5H), 9.37 (s,1H), 10.53 (s,1H), 11.18 (s,1H).

EXAMPLE 844-(4-methoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylicacid hydroxyamide

2-[(2-Hydroxy-ethyl)-(3-methoxy-benzyl)-amino]-ethanol was preparedaccording to the general method as outlined in example 83. Starting fromdiethanolamine (3.1 g, 29.5 mmol) and 3-methoxybenzyl chloride (5 g,31.9 mmol). Yield 9.28 g, (99%); yellow oil; MS: 226 (M+H).

3-Methoxybenzyl-bis-(2-chloro-ethyl)-amine was prepared according to thegeneral method as outlined in example 83. Starting from 3-Methoxy-benzyldiethanolamine (4.4 g, 20 mmol). Yield 4.5 g (93%); yellow solid mp86-88 C; MS: 263. (M+H)⁺.

4-(4-Methoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)piperidine-4-carboxylicacid ethyl ester was prepared according to the general method asoutlined in example 83. Starting from 4-(methoxy-benzenesulfonyl)-aceticacid ethyl ester (5.0 g, 22 mmol) and bis-(2-chloroethyl)-(3-methoxy-benzyl)-amine (8.0 g, 23.5 mmol). Yield 2.4 g (24%);low melting solid; MS: 447.9 (M+H)⁺.

4-(4-Methoxy-benzenesulfonyl)1-(3-methoxy-benzyl)-piperidine-4-carboxylic acid was prepared startingfrom4-(4-Methoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)piperidine-4-carboxylicacid ethyl ester (2.4 g, 5.36 mmol) dissolve in methanol (30 mL), 10 Nsodium hydroxide (10 mL), tetrahydrohydrofuran (20 mL). The resultingreaction mixture was worked up as outlined in example 83. Yield 710 mg(32%). white solid mp 199° C., MS: 419.9 (M+H)⁺.

Starting from4-(4-methoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylicacid (830 mg, 1.98 mmol) and following the procedure as outlined inexample 83, 190 mg of4-(4-methoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylicacid hydroxamide was isolated as a white solid. mp 130° C.; Yield 20.4%;MS:

435.0 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ2.24-2.32 (m, 2H), 2.51(d,2H), 2.73-2.83 (m, 2H), 3.37 (d, 2H), 3.76 (s, 3H), 3.88 (s, 3H), 4.32(s, 2H), 7.01-7.77 (m,8H), 9.38 (s, 1H), 10.1 (s, 1H).

EXAMPLE 851-(3,4-dichlorobenzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid hydroxamide

2-[(2-Hydroxy-ethyl)-(3,4-dichloro-benzyl)-amino]-ethanol was preparedaccording to the general method as outlined in example 83. Starting fromdiethanolamine (4.84 g, 46 mmol) and 3,4dichlorobenzyl chloride (9.0 g,46 mmol). Yield 13.8 g (99%); colorless oil; MS: 264.3 (M+H)⁺.

3,4-Dichlorobenzyl-bis-(2-chloro-ethyl)-amine was prepared according tothe general method as outlined in example 83. Starting from3,4-dichlorobenzyl diethanolamine (10.7 g, 41 mmol). Yield 99%; yellowsolid mp 218-220° C.; MS: 301.8 (M+H)⁺.

1-(3,4-Dichloro-benzyl)-4-(methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method asoutlined in example 83. Starting from 4-(methoxy-benzenesulfonyl)-aceticacid ethyl ester (2.9 g, 11 mmol) and3,4dichlorobenzyl-bis(2-chloroethyl)-amine (3.4 g, 11 mmol). Yield 5.9 g(60%); brown oil; MS: 494.5 (M+H)⁺.

1-(3,4-Dichloro-benzyl)-4-(4-methoxy-benzenesulfulfonyl)-piperidine-4-carboxylicacid was prepared starting from1-(3,4-dichloro-benzyl)4-(methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid ethyl ester (5.0 g, 10 mmol) dissolved in methanol (50 mL), 10 Nsodium hydroxide (15 mL) and tetrahydrofuran (75 mL). The resultingreaction mixture was worked up as outlined in example 83. Yield 2.94 g(62%), MS: 458.3 (M+H)⁺.

Starting from1-(3,4-dichlorobenzyl)4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid (2.67 g, 5.8 mmol) and following the procedure as outlined inexample 83, 0.2 g of 1-(3,4-dichlorobenzyl)4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxamidewas isolated as a white solid. mp 192-195° C.; Yield 10%; MS 472.9(M+H)⁺;

¹H NMR (300 MHz, DMSO-d₆): δ2.20-2.28 (m, 2H), 2.76-2.79 (m, 2H),3.43-3.44 (m, 4H), 4.30 (s, 2H), 7.14-7.17 (d, J=0.030, 2H), 7.50-7.73(d, J=0.027, 1H), 7.65-7.68 (d, J=0029, 2H), 7.72-7.75 (d, J=0.027, 2H),7.87 (s, 1H), 9.37 (s, 1H), 10.53 (s, 1H), 11.8 (s, 1H).

EXAMPLE 864-(4-methoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylicacid hydroxamide

2-[(2-Hydroxy-ethyl)-(4-methyl-benzyl)-amino]-ethanol was preparedaccording to the general method as outlined in example 83. Starting fromdiethanolamine (4.8 g, 46 mmol) and 4-methylbenzyl chloride (8.5 g, 46mmol). Yield 9.8 g (99%); MS: 209.9 (M+H)⁺.

4-Methylbenzyl-bis-(2-chloro-ethyl)-amine was prepared according to thegeneral method as outlined in example 83. Starting from 4-methyl-benzyldiethanolamine (6 g, 20 mmol). Yield 5.2 g (84%); yellow solid mp145-147° C.; MS: 245.9 (M+H)⁺.

4-(4-Methoxy-benzenesulfonyl)-1-(4-methyl-benzyl)piperidine-4-carboxylicacid ethyl ester was prepared according to the general method asoutlined in example 83. Starting from 4-(methoxy-benzenesulfonyl)-aceticacid ethyl ester (7.0 g, 27 mmol) and4-methyl-bis-(2-chloro-ethyl)-amine (5.0 g, 17 mmol). Yield 4.64 g(63%); low melting solid; MS: 431.9 (M+H)⁺.

4-(4-Methoxy-benzenesulfonyl)1-(4-methyl-benzyl)-piperidine-4-carboxylic acid was prepared startingfrom 4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethylester (4.3 g, 9.9 mmol) dissolve in methanol (30 mL), 10 N sodiumhydroxide (10 mL), tetrahydrohydrofuran (20 mL). The resulting reactionmixture was worked up as outlined in is example 83. Yield 1.6 g (40%).white solid mp 207-208° C., MS: 404.3 (M+H)⁺.

Starting from4-(4-methoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylicacid (1.59 g, 3.9 mmol) and following the procedure as outlined inexample 83, .505 g of4-(4-methoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylicacid hydroxamide was isolated as a white solid. mp 176-177° C.; Yield32%; MS: 419.0 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d6): δ2.24-2.32 (m, 2H),2.51(t, 3H), 2.73-2.80 (m, 2H), 3.35-3.50 (m, 4H), 3.87 (s, 3H), 4.24(s, 2H), 7.13-7.17 (d, J=0.039, 2H), 7.23-7.60 (d, J=0.036, 2H),7.38-7.41 (d, J=0.025, 2H), 7.65-7.68 (d, J=0.039, 2H).

EXAMPLE 874-(4-methoxy-benzene-sulfonyl)-1-napthalene-2-yl-methylpiperidine-4-carboxylicacid hydroxamide

2-[(2-Hydroxy-ethyl)-(2-napthyl-2-ylmethyl)-amino]-ethanol was preparedaccording to the general method as outlined in example 83. Starting fromdiethanolamine (6.18 g, 59 mmol) and 2-(bromomethyl)napthalene (10 g, 45mmol). Yield 12.7 g (96%); yellow solid mp 162-164° C.; MS: 246.0(M+H)⁺.

2-Napthyl-2-ylmethyl-bis-(2-chloro-ethyl)-amine was prepared accordingto the general method as outlined in example 83. Starting from2-napthyl-ylmethyl-diethanol amine (10 g, 36 mmol). Yield 9.1 g (79%);brown solid mp 124-126° C.; MS: 281.9 (M+H)⁺.

4-(4-Methoxy-benzenesulfonyl)-napthalene-ylmethyl-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method asoutlined in example 83. Starting from 4-(methoxy-benzenesulfonyl)-aceticacid ethyl ester (8.4 g, 32 mmol) and1-napthalene-ylmethyl-bis-(2chloro-ethyl)-amine ((8.6 g, 27 mmol). Yield6.5 g (52%); low melting solid; MS: 440.0 (M+H)⁺.

4-(4-Methoxy-benzenesulfonyl)-1-napthalene-ylmethyl-piperidine-4-carboxylicacid was prepared starting from4-(4-methoxy-benzenesulfonyl)-napthalene-ylmethyl-piperidine-4-carboxylicacid ethyl ester (6.3 g, 13 mmol) dissolved in methanol (30 mL), 10 Nsodium hydroxide (30 mL) and tetrahydrofuran (30 mL). The resultingreaction mixture was worked up as outlined in example 83. Yield 2.3 g(36%). yellow solid mp 226-228° C., MS: 440.0 (M+H)⁺.

Starting from4-(4-methoxy-benzenesulfonyl)-1-napthalene-2-yl-methylpiperidine-4-carboxylicacid (2.18 g, 5.0 mmol) and following the procedure as outlined inexample 83, .753 g of4-(4-methoxy-benzene-sulfonyl)-1-napthalene-2-yl-methylpiperidine-4-carboxylicacid hydroxamide was isolated as a off white solid. mp 168-170° C.;Yield 31%; MS 455.0 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ2.29-2.33 (m,2H), 2.86-2.89 (m, 2H), 3.42-3.46 (m, 4H), 3.85 (s, 3H), 4.46 (s, 2H),7.13-7.16 (d, J=0.030, 2H), 7.56-7.64 (m, 3H), 7.65-7.68 (d, J=0.032,2H), 7.98-8.00 (m, 3H), 8.21 (s, 1H), 10.70 (s, 1H), 11.20 (s, 1H).

EXAMPLE 881-Biphenyl4-ylmethyl-4-(4-methoxy-benzenesulfonyl)piperidine-4-carboxylicacid hydroxamide

2-[(2-Hydroxy-ethyl)-(1-biphenyl-4-ylmethyl))-amino]-ethanol wasprepared according to the general method as outlined in example 83.Starting from diethanol amine (5.2 g, 49 mmol) and4-(chloromethyl)biphenyl (10 g, 49 mmol). Yield 9.98 a (66%); whitesolid mp 160-162° C.;

MS: 271.9 (M+H)⁺. This was converted to the dichloride as outlined inexample 83

1-Biphenyl-4-ylmethyl4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method asoutlined in example 83. Starting from 4-(methoxy-benzenesulfonyl)-aceticacid ethyl ester (2.85 g, 11 mmol) and1-biphenyl-4-ylmethyl-bis-(2chloro-ethyl)-amine (3.4 g, 11 mmol). Yield2.1 g, (39%); beige solid, mp 176-178° C., MS: 494.1 (M+H)⁺.

1-Biphenyl4-ylmethyl4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid was prepared starting from1-biphenyl-4ylmethyl-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid ethyl ester (5.7 g, 12 mmol) dissolved in ethanol (20 mL),tetrahydrofuran (20 mL) and 10 N sodium hydroxide (10 mL). The resultingreaction mixture was worked up as outlined in example 83. Yield 2.1 g(39% ) MS: 465.8 (M+H)⁺.

Starting from1-biphenyl4-ylmethyl4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid (1.0 g, 2.2 mmol and following the procedure as outlined in example83, 0.132 g of1-biphenyl4-ylmethyl4-(4-methoxy-benzenesulfonyl)piperidine-4-carboxylicacid hydroxamide was isolated as a tan solid. mp168° C.; Yield 20%; MS:440.9 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d6): δ2.30-2.35 (m, 2H), 2.83-2.87(m, 2H), 3.35-3.5 (m, 4H), 3.87 (s, 3H), 7.15-7.721 (d, J=0.059 Hz, 2H),7.49-7.65 (m, 5H), 7.68-7.74 (d, J=0.06 Hz, 2H), 9.3 (s, 1H), 10.3 (s,1H), 11.15 (s, 1H).

EXAMPLE 894-(4-methoxy-benzene-sulfonyl)-1-(3-methyl-but-2-enyl)piperidine-4-carboxylicacid hydroxamide

2-[(2-Hydroxy-ethyl)-1-(3-methyl-but-2-enyl)-amino]-ethanol was preparedaccording to the general method as outlined in example 83. Starting fromdiethanol amine (4.1 g, 39 mmol) and 4bromo-2-methyl-butene (6.0 g, 40mmol). Yield (98%); brown oil; MS: 173.8 (M+H)⁺.

1-(3-methyl-but-2-enyl)]-bis-(2-chloroethyl)-amine was preparedaccording to the general method as outlined in example 83. Starting from2-[(2-hydroxy-ethyl)-1-(3-methyl-but-2-enyl)-amino]-ethanol (10.4 g, 50mmol). Yield 10.5 g (99%); brown solid; MS: 210.3 (M+H)

4-(4-Methoxy-benzenesulfonyl)-1-(3-methyl-but-2-enyl)-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method asoutlined in example 1. Starting from 4-(methoxy-benzenesulfonyl)-aceticacid ethyl ester (11.32 g, 44 mmol) and3-methyl-but-2-enyl)-bis-(2-chloroethyl)-amine (10.4 g, 50 mmol). Yield6.2 g (36%); brown oil; MS: 395.6 (M+H)⁺.

4-(4-Methoxy-benzenesulfonyl)-1-(3-methyl-but-2-enyl)-piperidine-4-carboxylicacid was prepared staring from4-(4-methoxy-benzenesulfonyl)-1-(3-methyl-but-2-enyl)-piperidine-4-carboxylicacid ethyl ester (6.2 g, 16 mmol) dissolved in ethanol (15 mL), 10 Nsodium hydroxide (10 mL) and tetrahydrofuran (75 mL). The resultingreaction mixture was worked up as outlined in example 83. Yield 1.2 g(21%). brown solid mp 196-197° C., MS: 367.9 (M+H)⁺.

Starting from4-(4-methoxy-benzenesulfonyl)-1-(3-methyl-but-2-enyl)-piperidine-4-carboxylicacid (1.0 g. 3.0 mmol) and following the procedure as outlined inexample 83, 0.110 mg of4-(4-methoxy-benzene-sulfonyl)-1-(3-methyl-but-2-enyl)piperidine-4-carboxylicacid hydroxamide was isolated as a yellow solid. mp 142-145° C.; Yield12%; MS: 382.9 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ1.67 (s, 3H), 1.79(s, 3H), 2.18-2.23 (m, 2H), 2.66-2.73 (m, 2H), 3.37-3.46 (m, 2H),3.67-3.69 (m, 2H), 5.19-5.24 (m, 1H), 7.15-7.18 (d, J=0.03, 2H),7.67-7.70 (d, J=0.030, 2H), 9.34 (s, 1H), 9.88 (s, 1H), 11.15 (s, 1H).

EXAMPLE 901-(4-Bromo-benzyl)4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid hydroxyamide

2-[(4-Bromobenzyl)-(2-hydroxy-ethyl)-amino]-ethanol was preparedaccording to the general method as outlined in example 83. Starting fromdiethanolamine (22.5 g,, 150 mmol). and 4-bromobenzyl bromide (25 g, 100mmol). Yield 33.66 g, (99%); yellow oil; MS: 273.8 (M+H)⁺.

(4-Bromo-benzyl)-bis-(2-chloro-ethyl)-amine was prepared according tothe general method as outlined in example 83. Starting from2-[(4-bromobenzyl)-(2-hydroxy-ethyl)-amino]-ethanol (33.28 g, 122 mmol).Yield 47 g, (99%); brown solid; mp 125° C.; MS: 309.8 (M+H)⁺.

1-(4-Bromo-benzyl)4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method asoutlined in example 83. Starting from 4-(methoxy-benzenesulfonyl) aceticacid ethyl ester (8.6 g, 33.5 mmol) and(4-bromo-benzyl)-bis-(2-chloroethyl)-amine (13.3 g, 38.6 mmol). Yield 17g (44%); brown oil; MS: 497.8 (M+H)⁺.

1-(4-Bromo-benzyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid was prepared starting from1-(4-bromo-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid ethyl ester (16.5 g, 33.3 mmol) dissolved in THF:methanol 3:1 and10 N NaOH (20 ml). The resulting reaction mixture was worked up asoutlined in example 83. Yield 6.18 g (40%); tan solid; mp 215° C.; MS:469.7 (M+H)⁺.

Starting from1-(4-Bromo-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid (1.95 g, 4.2 mmol) and following the procedure as outlined inexample 83, 1.29 g of1-(4-bromo-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid hydroxyamide was isolated as an off white solid. Yield 60%; mp 180°C.; MS: 484.7 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ2.18-2.29 (m, 2H),2.46 (d, 2H), 2.74-2.89 (m, 2H), 3.39 (d, 2H), 3.87 (s, 3H), 4.28 (s,2H), 7.18 (d, J=17 Hz, 2H), 7.49 (d, J=8.1 Hz, 2H), 7.65-7.68 (m, 4H),9.37 (s, 1H), 10.5 (s, 1H).

EXAMPLE 914-(4-methoxy-benzenesulfonyl)-1-(3-phenyl-propyl)-piperidine-4-carboxylicacid hydroxyamide

2-[(2-Hydroxy-ethyl)-(3-phenyl-propyl)-amino]-ethanol was preparedaccording to the general method as outlined in example 83. Starting fromdiethanolamine (15.8 g, 151 mmol). and 1-bromo-3-phenylpropane (20 g,101 mmol). Yield 21.31 g, (95%); yellow oil; MS: 223.9 (M+H)⁺.

Bis-(2-Chloro-ethyl)-(3-phenyl-propyl)-amine was prepared according tothe general method as outlined in example 83. Starting from2-[(2-hydroxy-ethyl)-(3-phenyl-propyl)-amino]-ethanol (20.32 g, 90.7mmol). Yield 24.9 g (92%); brown oil; MS: 259.8 (M+H)⁺.

4-(4-Methoxy-benzenesulfonyl)-1-(3-phenyl-propyl)-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method asoutlined in example 83. Starting from from 4-(methoxy-benzenesulfonyl)acetic acid ethyl ester (12 g, 46.5 mmol) andbis-(2-chloro-ethyl)-(3-phenyl-propyl)-amine (24.8 g, 93.8 mmol). Yield11.24 g (54%); brown oil; MS: 446 (M+H)⁺.

4-(4-Methoxy-benzenesulfonyl)-1-(3-phenyl-propyl)-piperidine-4-carboxylicacid was prepared starting from4-(4-Methoxy-benzenesulfonyl)-1-(3-phenyl-propyl)-piperidine-4-carboxylicacid ethyl ester (10.74 g, 24.13 mmol) dissolved in THF:methanol 3:1 and10 N NaOH (40 ml). The resulting reaction mixture was worked up asoutlined in example 83. Yield 4.67 g (47%); off white powder; mp 203°C.; MS: 418.2 (M+H)⁺.

Starting from4-(4-methoxy-benzenesulfonyl)-1-(3-phenyl-propyl)-piperidine-4-carboxylicacid (4.37 g, 10.4 mmol) and following the procedure as outlined inexample 83, 1.64 g of4-(4-methoxy-benzenesulfonyl)-1-(3-phenyl-propyl)-piperidine-4-carboxylicacid hydroxyamide was isolated as an off white solid. Yield 37%; mp 143°C.; MS: 432.9 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ1.92-1.97 (m, 2H),2.18-2.29 (m, 2H), 2.47 (d, 2H), 2.58 (t, J=7.7 Hz, 2H), 2.6-2.73 (m,2H), 3.0-3.06 (m, 2H), 3.60 (d, J=12.3 Hz, 2H), 3.87 (s, 2H), 7.15-7.30(m, 7H), 7.68, (d, J=9 Hz, 2H), 9.3 (s, 1H), 10.1 (s, 1H).

EXAMPLE 921-Tert-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide

tert-Butyl-bis-(2-chloro-ethyl)-amine was prepared according to thegeneral method as outlined in example 83. Starting from1-tert-butyl-diethanolamine (6 g, 37.2 mmol). Yield 11.15 g, (99%);white solid; MS: 197.8 (M+H)⁺.

1-tert-Butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidethyl ester was prepared according to the general method as outlined inexample 83. Starting from 4-(methoxy-benzenesulfonyl) acetic acid ethylester (10 g, 38.76 mmol) and tert-butyl-bis-(2-chloro-ethyl)-amine (5.25g, 22.53 mmol). Yield 5.37 g, (62%); brown oil; MS: 384 (M+H)⁺.

1-tert-Butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidwas prepared starting from1-tert-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidethyl ester (5.37 g 14 mmol) dissolved in methanol (300 ml) and 10 NNaOH (23 ml). The resulting reaction mixture was worked up as outlinedin example 83. Yield 1.52 g (30.6%); white powder; mp 204° C.; MS: 356(M+H)⁺.

Starting from1-tert-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid(320 mg, 0.9 mmol) and following the procedure as outlined in example83, 190 mg of1-tert-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide was isolated as a green solid. Yield 52%; mp 40° C.; MS:371.1 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ1.29 (s, 9H), 1.54 (m, 2H),1.66 (m, 2H), 2.39 (m, 2H), 2.98 (m, 2H), 3.88 (s, 3H), 7.18 (d, 2H),7.67 (d, 2H).

EXAMPLE 93 1-Butyl4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid hydroxyamide

Butyl-bis-(2-chloro-ethyl)-amine was prepared according to the generalmethod as outlined in example 83. Starting from N-butyldiethanolamine (6g, 37.2 mmol). Yield 11.3 g, (99%); white powder; mp 165° C.; MS: 197.9(M+H)⁺.

1-Butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethylester was prepared according to the general method as outlined inexample 83. Starting from 4-(methoxy-benzenesulfonyl) acetic acid ethylester (5 g, 19.38 mmol) and butyl-bis-(2-chloro-ethyl)-amine (4.52 g,19.38 mmol). Yield 6.86 g, (93%); brown oil; MS: 384 (M+H)⁺.

1-Butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid wasprepared starting from1-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethylester (6.42 g 16.8 mmol) dissolved in methanol (200 ml) and 10 N NaOH(20 ml). The resulting reaction mixture was worked up as outlined inexample 83. Yield 1.6 (27%); white powder; mp 206 ° C.; MS: 356.4(M+H)⁺.

Starting from1-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid (1.51g, 4.3 mmol) and following the procedure as outlined in example 83, 200mg of 1-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide was isolated as an off white solid. Yield 9.3%; mp 75° C.;MS: 371.1 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆: δ0.87 (t, J=7.2 Hz, 3H),1.27 (m, 2H), 1.59 (m, 2H), 2.27 (m, 2H), 2.45 (m, 2H), 2.50 (m, 2H),2.65 (m, 2H), 2.97 (m, 2H) 3.88 (s, 3H), 7.18 (d, 2H), 7.69 (d, 2H).

EXAMPLE 941-Cyclooctyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide

Cyclooctyl-bis-(2chloro-ethyl)-amine was prepared according to thegeneral method as outlined in example 83. Starting fromN-cyclooctyldiethanolamine (6 g, 28 mmol). Yield 10 g, (99%); off whitesolid; mp 158° C.; MS: 251.9 (M+H)⁺.

1-Cyclooctyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidethyl ester was prepared according to the general method as outlined inexample 83. Starting from 4-(methoxy-benzenesulfonyl) acetic acid ethylester (5 g, 19.4 mmol) and cyclooctyl-bis-(2-chloro-ethyl)-amine (5.57g, 19.4 mmol). Yield 8.2 g, (96%); brown oil; MS: 438 (M+H)⁺.

1-Cyclooctyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidwas prepared starting from1-cyclooctyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidethyl ester (8 g, 18.3 mmol) dissolved in methanol (200 ml) and 10 NNaOH (25 ml). The resulting reaction mixture was worked up as outlinedin example 83. Yield 2.36 g (32%); white powder; mp 180° C.; MS: 410(M+H)⁺.

Starting from1-Cyclooctyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid(2.26 g, 5.53 mmol) and following the procedure as outlined in example83, 570 mg of1-cyclooctyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide was isolated as a white powder. Yield 22%; mp >200° C.; MS:425 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ1.42-1.66 (m, 14H), 1.83 (m,2H), 2.33 (m, 2H), 2.67 (m, 2H), 3.30-3.51 (m, 3H) 3.88 (s, 3H) 7.17 (d,2H), 7.66 (d, 2H).

EXAMPLE 95 1-Ethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid hydroxyamide

1-Ethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethylester was prepared according to the general method as outlined inexample 83. Starting from 4-(methoxy-benzenesulfonyl) acetic acid ethylester (3 g, 11.6 mmol) and ethyl-bis-(2-chloro-ethyl)-amine (2.39 g,11.6 mmol). Yield 3.09 g, (75%); low melting brown solid; MS: 356(M+H)⁺.

1-Ethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid wasprepared starting from1-ethyl4-(methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethylester (2.42 g, 6.8 mmol) dissolved in methanol (100 ml) and 10 N NaOH(15 ml). The resulting reaction mixture was worked up as outlined inexample 83. Yield 1.29 g (58%); white solid; mp 209° C.; MS: 328 (M+H)⁺.

Starting from1-ethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid (1.23g, 3.76 mmol) and following the procedure as outlined in example 83,1.02 g of 1-ethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid hydroxyamide was isolated as an off white powder. Yield 80%; mp 85°C.; MS: 343 (M+H)⁺; ¹H NMR (300 M , DMSO-d6): δ0.926 (t, J=7.1 Hz, 3H),1.68-1.89 (m, 4H), 2.05-2.24 (m, 4H), 2.73 (q, 2H), 3.85 (s, 3H), 7.07(d, 2H), 7.64 (d, 2H).

EXAMPLE 961-Isopropyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide

1-Isopropyl4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidethyl ester was prepared according to the general method as outlined inexample 83. Starting from 4-(methoxy-benzenesulfonyl) acetic acid ethylester (5.7 g, 22.2 mmol) and isopropyl-bis-(2-chloro-ethyl)-amine (4.9g, 22.2 mmol). Yield 5.64 g, (68%); low melting brown solid; MS: 370(M+H)⁺.

1-Isopropyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidwas prepared starting from1-isopropyl4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidethyl ester (5.6 g, 15.2 mmol) dissolved in methanol (75 ml) and 10 NNaOH (25 ml). The resulting reaction mixture was worked up as outlinedin example 83. Yield 2.18 g (42%); white powder; mp 204 ° C.; MS: 341.9(M+H)⁺.

Starting from1-isopropyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid(2.13 g, 6.25 mmol) and following the procedure as outlined in example83, 590 mg of1-isopropyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide was isolated as a white powder. Yield 2.4%; mp 75° C.; MS:357 (M+H)⁺; ¹H NMR (300 MH, DMSO-d₆: δ1.21 (d, J=6.6 Hz, 6H), 2.33-3.53(m, 9H), 3.88 (s, 3H), 7.16 (d, 2H), 7.66 (d, 2H).

EXAMPLE 971-Methyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide

1-Methyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acidethyl ester was prepared according to the general method as outlined inexample 83. Starting from ⁴-(methoxy-benzenesulfonyl) acetic acid ethylester (3 g, 11.6 mmol) and methyl-bis-(2-choro-ethyl)-amine (2.2 g, 11.6mmol). Yield 3.09 g, (75%); low melting brown solid; MS: 342 (M+H)⁺.

1-Methyl(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid wasprepared starting from1-methyl4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethylester (8.7 g, 25.6 mmol) dissolved in methanol (300 ml) and 10 N NaOH(35 ml). The resulting reaction mixture was worked up as outlined inexample 83. Yield 3.23 g (41%); white solid; mp 204 ° C.; MS: 313.9(M+H)⁺.

Starting from1-methyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid (2.0g, 6.38 mmol) and following the procedure as outlined in example 83,1.10 g of 1-methyl4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid hydroxyamide was isolated as a yellow powder. Yield 53%; mp 89° C.;MS: 329 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ1.67-1.76 (m, 2H), 1.85-1.96(m, 2H), 2.05 (s, 3H), 2.17 (d, J=11.4 Hz, 2H), 2.57 (d, J=10.4 Hz, 2H)3.83 (s, 3H), 7.02 (d, 2H), 7.62 (d, 2H).

EXAMPLE 98 1-Benzyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylicacid hydroxyamide

1-Benzyl(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethylester was prepared according to the general method as outlined inexample 83. Starting from from 4-(butoxy-benzenesulfonyl) acetic acidethyl ester (6 g, 20 mmol) and bis-(2-chloro-ethyl)-benzylamine (10 g,30 mmol). Yield 5.15 g (56%); yellow oil; MS: 460 (M+H)⁺.

1-Benzyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid wasprepared starting from1-benzyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethylester (5.1 g, 11.1 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (10ml). The resulting reaction mixture was worked up as outlined in example83. Yield 2.66 g (56%); off white solid; mp 210° C.; MS: 432 (M+H)⁺.

Starting from1-benzyl4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid (2.61g, 6.06 mmol) and following the procedure as outlined in example 83, 860mg of 1-benzyl4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide was isolated as an off white powder. Yield 32%; mp 144° C.;MS: 446.9 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ0.94 (t, J=7.3 Hz, 3H),1.44 (q, J=7.5 Hz, 2H), 1.70 (q, 2H), 2.28-2.32 (m, 2H), 2.50 (d, 2H),2.74-2.83 (m, 2H), 3.35 (d, 2H), 4.08 (t, J=6.3 Hz, 2H), 4.34 (s, 2H),7.13 (d, J=8.7, 2H), 7.45 (s, 3H), 7.54 (s, 2H), 7.74 (d, J=8.7, 2H),9.35 (s, 1H), 10.7 (s, 1H).

EXAMPLE 991-(4-Fluoro-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid hydroxyamide

1-(4-Fluoro-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method asoutlined in example 83. Starting from 4-(methoxy-benzenesulfonyl) aceticacid ethyl ester (18.8 g, 72.8 mmol) and(4-fluoro-benzyl)-bis-(2-chloro-ethyl)-amine (20.8 g, 73 mmol). Yield 25g (79%); brown oil; MS: 436.9 (M+H)⁺.

1-(4-Fluoro-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid was prepared starting from1-(4-fluoro-benzyl)4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid ethyl ester (17.4 g, 40 mmol) dissolved in THF:methanol 3:1 and 10N NaOH (40 ml). The resulting reaction mixture was worked up as outlinedin example 83. Yield 10.8 g (66%); colorless solid; mp 154° C.; MS: 408(M+H)⁺.

Starting from1-(4-Fluoro-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid (8.14 g, 20 mmol) and following the procedure as outlined inexample 83, 4.3 g of1-(4-fluoro-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid hydroxyamide was isolated as an off white solid. Yield 51%; mp176-178° C.; MS: 484.7 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ2.12-2.20 (m,2H), 2.64-2.79 (m, 2H), 3.32-3.45 (m, 4H), 3.87 (s, 3H), 4.31 (s, 2H),7.14-7.19 (d, J=17 Hz, 2H), 7.27-7.33 (d, J=8.1 Hz, 2H), 7.50-7.54 (d,2H), 7.65-7.68 (d, 2H), 9.38 (s, 1H), 9.75 (s, 1H).

EXAMPLE 1001-(4-Fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylicacid hydroxyamide

1-(4-Fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method asoutlined in example 83. Starting from from 4-(butoxy-benzenesulfonyl)acetic acid ethyl ester (6 g, 20 mmol) and(4-fluoro-benzyl)-bis-(2-chloro-ethyl)-amine (5.73 g, 20 mmol). Yield8.2 g (86%); yellow oil; MS: 478 (M+H)⁺.

1-(4-Fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylicacid was prepared starting from1-(4Fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylicacid ethyl ester (4.77 g, 10 mmol) dissolved in THF:methanol 3:1 and 10N NaOH (10 ml). The resulting reaction mixture was worked up as outlinedin example 83. Yield 3.5 g (79%); off white solid; mp 114° C.; MS: 450(M+H)⁺.

Starting from1-(4-Fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylicacid (2.24 g, 5.0 mmol) and following the procedure as outlined inexample 83, 200 mg of1-(4-Fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylicacid hydroxyamide was 10 isolated as an off white powder. Yield 9%; mp112° C.; MS: 465.9 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ0.94 (t, J=7.3Hz, 3H), 1.35-1.50 (m, 2H), 1.68-1.77 (m, 2H), 2.20-2.28 (m, 2H),2.66-2.77 (m, 2H), 3.77-3.78 (m, 4H), 4.06-4.10 (m, 2H), 4.19 (s, 2H),7.14-7.19 (d, J=8.7, 2H), 7.27-7.33 (d, 2H), 7.50-7.54 (d, 2H),7.65-7.68 (d, 2H), 9.34 (s, 1H), 10.55 (s, 1H).

EXAMPLE 1014-(4-methoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4-carboxylicacid hydroxyamide

2-[(2-Hydroxy-ethyl)-(4-methoxy-benzyl)-amino]-ethanol was preparedaccording to the general method as outlined in example 83. Starting fromdiethanolamine (12.0 g, 114 mmol) and 4-methoxybenzyl chloride (14.2 g,100 mmol). Yield 17.5 g, (77%); yellow oil; MS: 226 (M+H).

4Methoxybenzyl-bis-(2-chloro-ethyl)-amine was prepared according to thegeneral method as outlined in example 83. Starting from 4Methoxy-benzyldiethanolamine (10 g, 44 mmol). Yield 10 g (75%); yellow solid mp 55 C;MS: 263.1 (M+H)⁺.

4-(4-Methoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)piperidine-4-carboxylicacid ethyl ester was prepared according to the general method asoutlined in example 83. Starting from 4-(methoxy-benzenesulfonyl)-aceticacid ethyl ester (5.0 g, 20 mmol) and bis-(2chloroethyl)-(4-methoxy-benzyl)-amine (7.0 g, 22 mmol). Yield 5.0 g (56%); lowmelting solid; MS: 448.5 (M+H)⁺.

4-(4Methoxy-benzenesulfonyl)1-(4-methoxy-benzyl)-piperidine-4-carboxylicacid was prepared starting from4-(4Methoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)piperidine-4carboxylicacid ethyl ester (4.2 g, 10 mmol) dissolve in methanol (30 mL), 10 Nsodium hydroxide (10 mL), tetrahydrohydrofuran (20 mL). The resultingreaction mixture was worked up as outlined in example 83. Yield 3.0 g(71%). white solid mp 190° C., MS: 420.4 (M+H)⁺.

Starting from4(4-methoxy-benzenesulfonyl)-1-(4methoxy-benzyl)-piperidine-4-carboxylicacid (2.0 g, 4.7 mmol) and following the procedure as outlined inexample 83, 1.2 g of 4-(4methoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine4carboxylic acidhydroxamide was isolated as a white solid. mp 175° C. (HCl); Yield: 1.2g, 59%; MS: 433.0 (M+H)⁺; ¹H NM (300 MHz, DMSO-d₆): δ1.8 (m, 4H), 2.3(m,2H), 2.73 (m, 2H) 3.37 (d, 2H), 3.76 (s, 3H), 3.88 (s,3H), 6.87 (d, 2H),7.11 (d, 2H), 7.21 (d 2H), 9.2 (bs, 1H), 10.9 (bs, 1H).

EXAMPLE 1024-(4-methoxy-benzenesulfonyl)-1-[2-(4-methoxyphenyl)-ethyl]-piperidine-4-carboxylicacid hydroxyamide

2-{(2-Hydroxy-ethyl)-[2-(4-methoxy-phenyl)-ethyl]-amino}-ethanol wasprepared according to the general method as outlined in example 83.Starting from diethanolamine (10.0 g, excess). and1-(2-chloroethyl)4-methoxy benzene (8.5 g, 50 mmol). Yield 11 g, (92%);yellow oil; MS: 240 (M+H)⁺.

The corresponding dichloride,bis-(2-chloro-ethyl)-(4-methoxyphenyl-2-ethyl)-amine was preparedaccording to the general method as outlined in example 83. Starting from2-{(2-hydroxy-ethyl)-[2-(4-methoxy-phenyl)-ethyl]-amino }-ethanol (10 g,41.8 mmol). Yield 11 g (95%); brown oil; MS: 277.2 (M+H)⁺.

4(4methoxy-benzenesulfonyl)-1-[2-(4methoxyphenyl)-ethyl]-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method asoutlined in example 83. Starting from from 4(methoxy-benzenesulfonyl)acetic acid ethyl ester (5.0 g, 20 mmol) andbis-(2-chloro-ethyl)-(4-methoxyphenyl-2-ethyl)-amine (6.4 g, 20 mmol).Yield 6.0 g (65%); brown oil; MS: 462.5 (M+H)⁺.

4(4methoxy-benzenesulfonyl)-1-[2-(4methoxyphenyl)-ethyl]-piperidine-4carboxylicacid was prepared starting from4-(4-methoxy-benzenesulfonyl)-1-[2-(4-methoxyphenyl)-ethyl]-piperidine-4-carboxylicacid ethyl ester (5.0 g, 10.8 mmol) dissolved in THF:methanol 3:1 and 10N NaOH (40 ml). The resulting reaction mixture was worked up as outlinedin example 83.

Yield 4.0 g (85%); off white powder; mp 205° C.; MS: 434.5 (M+H)⁺.

Starting from4-(4-methoxy-benzenesulfonyl)-1-[2-(4-methoxyphenyl)-ethyl]-piperidine-4-carboxylicacid (1.5 g, 3.46 mmol) and following the procedure as outlined inexample 83, 900 mg of4-(4methoxy-benzenesulfonyl)-1-[2-(4methoxyphenyl)-ethyl]-piperidine-4-carboxylicacid hydroxyamide was isolated as an off white solid. Yield 58%; mp 206°C. (HCl); MS: 449.5 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ2.3 (m, 2H), 2.5(m, 3H), 2.8 (m, 2H), 2.95 (m, 2H), 3.25 (m, 2H), 3.4 (m,4H), 3.60 (d,J=12.3 Hz, 2H), 3.77 (s, 3H), 6.9 (d, 2H), 7.1-7.25, (q, 4H), 7.7 (d,2H), 9.3 (s, 1H), 10.6 (s, 1H).

EXAMPLE 1034-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidine-4-carboxylicacid hydroxyamide

2-[(2-Hydroxy-ethyl)-(2-phenyl-ethyl)-amino]-ethanol was preparedaccording to the general method as outlined in example 1. Starting fromdiethanolamine (6.0 g, 57). and 2-bromo-ethylbenzene (9.0 g, 48.3 mmol).Yield 9 g, (90%); yellow oil; MS: 210 (M+H)⁺.

Bis-(2-Chloro-ethyl)-(2-phenyl-ethyl)-amine was prepared according tothe general method as outlined in example 83. Starting from2-[(2-Hydroxy-ethyl)-(2-phenyl-ethyl)-amino]-ethanol (8.5 g, 40.6 mmol).Yield 11 g (95%); brown oil; MS: 247.1 (M+H)⁺.

4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method asoutlined in example 83. Starting from from 4-(methoxy-benzenesulfonyl)acetic acid ethyl ester (5.0 g, 20 mmol) andbis-(2-chloro-ethyl)-(2-phenyl-ethyl)-amine (5.6 g, 20 mmol). Yield 5.5g (63%); brown oil; MS: 432.5 (M+H)⁺.

4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidine-4-carboxylicacid was prepared starting from4(4methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidine-4-carboxylicacid ethyl ester (3.0 g, 6.9 mmol) dissolved in THF:methanol 3:1 and 10N NaOH (40 ml). The resulting reaction mixture was worked up as outlinedin example 83. Yield 2.0 g (72%); off white powder; mp 208° C.; MS:404.5 (M+H)⁺.

Starting from4-(4methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidine-4-carboxylicacid (1.5 g, 3.7 mmol) and following the procedure as outlined inexample 83, 900 mg of4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidine-4carboxylicacid hydroxyamide was isolated as an off white solid. Yield 58%; mp 205°C. (HCl); MS: 419.4 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ2.3 (m, 2H), 2.5(m, 3H), 2.8 (m, 2H), 2.95 (m, 2H) 2H), 3.4 (m,4H), 3.9 (s, 3H),7.22-7.8(m, 9H), 10.6 (s, 1H), 11.2 (bs, 1H).

EXAMPLE 1044-(1n-Butoxy-benzenesulfonyl)-1-(4-methoxy-benzy1)-piperidine-4-carboxylicacid hydroxyamide

4-(4-n-Butoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)piperidine-4-carboxylicacid ethyl ester was prepared according to the general method asoutlined in example 83. Starting from4-(n-Butoxy-benzenesulfonyl)-acetic acid ethyl ester (2.5 g, 10 mmol)and bis-(2-chloro ethyl)-(4-methoxy-benzyl)-amine (3.0 g, 10 mmol).Yield 3.5 g (71%); low melting solid; MS: 490.5 (M+H)⁺.

4-(4-n-Butoxy-benzenesulfonyl)1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid was prepared startingfrom4-(4-Butoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)piperidine-4-carboxylicacid ethyl ester (3.0 g, 6.1 mmol) dissolve in methanol (30 mL), 10 Nsodium hydroxide (10 mL), tetrahydrohydrofuran (20 mL). The resultingreaction mixture was worked up as outlined in example 83. Yield 1.5 g(53%). white solid mp 207° C., MS: 462.5 (M+H)⁺.

Starting from4-(4-n-Butoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4-carboxylicacid (1.0 g, 2.1 mmol) and following the procedure as outlined inexample 83, 1.2 g of4-(4-Butoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4-carboxylicacid hydroxamide was isolated as a white solid. mp 173° C. (HCl); Yield:800 mg, 77%; MS: 477.5 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ0.9 (t, 3H),1.4 (m, 2H), 1.7 (m,2H), 2.3 (m, 2H), 2.5 (m, 2H), 2.7 (in, 2H), 3.3 (m,2H), 3.5(m, 2H), 4.1 (t, 2H), 6.97 (d, 2H), 7.14 (d, 2H), 7.48 (d, 2H),7.7 (d, 2H), 9.4 (bs, 1H), 10.9 (bs, 1H).

EXAMPLE 1054-(4-Methoxy-benzenesulfonyl)-1-(3-phenoxy-ProPyl)-piperidine-4-carboxylicacid hydroxyamide

2-[(2-Hydroxy-ethyl)-(3-phenoxy-propyl)-amino]-ethanol was preparedaccording to the general method as outlined in example 83. Starting fromdiethanolamine (15.8 g, 151 mmol). and 3-Phenoxypropyl bromide (21.5 g,100 mmol). Yield 21.31 g, (95%); yellow oil; MS: 238.1 (M+H)⁺.

Bis-(2-Chloro-ethyl)-(3-phenoxy-propyl)-ane was prepared according tothe general method as outlined in example 83. Starting from2-[(2-hydroxy-ethyl)-(3-phenoxy-propyl)-amino]-ethanol (20.0 g, 84mmol). Yield 24.0 g (91%); brown oil; MS: 277.8 (M+H)⁺.

4(4-Methoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method asoutlined in example 83. Starting from from 4(methoxy-benzenesulfonyl)acetic acid ethyl ester (5.2 g, 20 mmol) andbis-(2-chloro-ethyl)-(3-phenoxy-propyl)-amine (7.0 g, 22 mmol). Yield6.5 g (70%); brown oil; MS: 462.5 (M+H)⁺.

4-(4-Methoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylicacid was prepared starting from⁴-(⁴-Methoxy-benzenesulfonyl)-1-(³-phenoxy-propyl)-piperidine-4-carboxylicacid ethyl ester (4.2 g, 9.1 mmol) dissolved in THF:Methanol 3:1 and 10N NaOH (40 ml). The resulting reaction mixture was worked up as outlinedin example 83. Yield 3.0 g (75%); off white powder; mp 195° C.; MS:434.5 (M+H)⁺.

Starting from4-(⁴-methoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine4-carboxylicacid (2.5 g, 5.77 mmol) and following the procedure as outlined inexample 83, 1.2 g of4-(4-methoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylicacid hydroxyamiide was isolated as an off white solid. Yield 46%; mp101° C.; MS: 448.5 (M+H)⁺; ¹H NMR (300 Hz, DMSO-d₆): δ2.18 (m, 2H), 2.3(m, 2H), 2.58 (m, 2H), 2.6-2.73 (m, 2H), 3.0-3.06 m, 2H), 3.60 (m 2H),3.87 (s, 3H), 4.01 (t, 2H), 6.9-7.7 (m, 9H), 9.33 (bs, 1H), 10.28 bs,1H).

EXAMPLE 1064-(4-n-Butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylicacid hydroxyamide

4-(4-n-Butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method asoutlined in example 83. Starting from from 4-(butoxy-benzenesulfonyl)acetic acid ethyl ester (3.0 g, 10 mmol) andbis-(2-chloroethyl)-(3-phenoxy-propyl)-amine (3.0 g, 11 mmol). Yield 4.5g (89%); brown oil; MS: 504.6 (M+H)⁺.

4-(4-n-Butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylicacid was prepared starting from4(4-n-Butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylicacid ethyl ester (4.0 g, 7.9 mmol) dissolved in THF:Methanol 3:1 and 10N NaOH (40 ml). The resulting reaction mixture was worked up as outlinedin example 83. Yield 3.0 g (79%); off white powder; mp 191° C.; MS:476.5 (M+H)⁺.

Starting from4-(4-n-butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylicacid (700 mg, 1.4 mmol) and following the procedure as outlined inexample 83, 300 mg of4-(4-n-butoxy-benzenesulfonyl)-1-3-phenoxy-propyl)-piperidine-4-carboxylicacid hydroxyamide was isolated as an off white solid. Yield 43%; mp 84°C.; MS: 491.5 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ0.9 (t, 3H), 1.5 (m,2H), 1.8 (m, 2H), 2.18 (m, 2H), 2,3 (m, 2H), 2.58 (m, 2H), 2.6-2.73 (m,2H), 3.2 (m, 2H), 3.40 (m 6H), 3.97 (t, 2H), 6.9-7.7 (m, 9H), 10.7 (bs,1H), 11.28 (bs, 1H).

EXAMPLE 1074-(4-methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylicacid hydroxyamide

2-[(2-Hydroxy-ethyl)-(2-phenoxy-ethyl)-amino]-ethanol was preparedaccording to the general method as outlined in example 83. Starting fromdiethanolamine (15.0 g, 150). and 2chloro-phenetol (15.6 g, 100 mmol).Yield 18 g, (80%); Colorless oil; MS: 226 (M+H)⁺.

Bis-(2-Chloro-ethyl)-(2-phenoxy-ethyl)-amine was prepared according tothe general method as outlined in example 83. Starting from2-[(2-Hydroxy-ethyl)-(2-phenoxy-ethyl)-amino]-ethanol (20.0 g, 88.8mmol). Yield 25 g (94%); brown oil; MS: 263.1 (M+H)⁺.

4-(4methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method asoutlined in example 83. Starting from from 4-(methoxy-benzenesulfonyl)acetic acid ethyl ester (5.0 g, 20 mmol) andbis-(2-chloro-ethyl)-(2-phenoxy-ethyl)-amine (6.0 g, 20 mmol). Yield 5.8g (64%); brown oil; MS: 448.5 (M+H)⁺.

4-(4methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine carboxylicacid was prepared starting from4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethoxy)-piperidine-4-carboxylicacid ethyl ester (5.0 g, 11.1 mmol) dissolved in THF:methanol 3:1 and 10N NaOH (40 ml). The resulting reaction mixture was worked up as outlinedin example 83. Yield 3.0 g (63%); off white powder; mp 235° C.; MS:420.5 (M+H)⁺.

Starting from4-(4-methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylicacid (2.5 g, 5.9 mmol) and following the procedure as outlined inexample 83, 1.3 g of4(4-methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylicacid hydroxyamide was isolated as an off white solid. Yield 50%; mp168-172° C. (HCl); MS: 435.4 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ2.3 (m,2H), 2.5 (m, 2H), 2.9 (m, 2H), 3.4 (m, 4H), 3.5 (m, 2H), 3.7 (m,2H), 3.9(s, 3H), 4.4 (m, 2H), 6.9-7.8 (m, 9H), 9.3 (s, 1H), 102 (bs, 1H), 11.3(s, 1H).

EXAMPLE 1084(4-n-Butoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylicacid hydroxyamide

4(4Butoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method asoutlined in example 83. Starting from from 4-(methoxy-benzenesulfonyl)acetic acid ethyl ester (2.5 g, 10 mmol) andbis-(2-chloro-ethyl)-(2-phenoxy-ethyl)-amine (2.98 ,, 10 mmol). Yield3.0 g (69%); brown oil; MS: 490.6 (M+H)⁺.

4(4n-Butoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylicacid was prepared starting from4-(4-n-butoxy-benzenesulfonyl)-1-(2-phenyl-ethoxy)-piperidine-4-carboxylicacid ethyl ester (2.5 g, 5.76 mmol) dissolved in THF:methanol 3:1 and 10N NaOH (40 ml). The resulting reaction mixture was worked up as outlinedin example 83. Yield 1.5 g (56%); off white powder; mp 204° C.; MS:462.5 (M+H)⁺.

Starting from4-(4-n-butoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylicacid (1.0 g, 2.16 mmol) and following the procedure as outlined inexample 83, 600 mg of4-(4butoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylicacid hydroxyamide was isolated as an off white solid. Yield 58%; mp 112°C. (HCl); MS: 477.4 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ0.942 (t, 3H),1.4 (m, 2H), 1.7 (m, 2H), 2.3 (m, 2H), 2.5 (m, 4H), 2.8 (m, 2H), 2.9-3.4(m, 4H), 3.3 (m, 4H), 4.2 (t, 2H), 4.4 (m, 2H), 6.9-7.7 (m, 9H), 9.4 (s,1H), 10.5 (bs, 1H), 11.3 (s, 1H).

EXAMPLE 1094-(4-Methoxy-benzenesulfonyl)-1-[4(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylicacid hydroxyamide

Bis-(2-chloro-ethyl)-[4-(2-piperdin-1-yl-ethoxy)-benzyl]-amine wasprepared according to the general method as outlined in example 83.Starting from diethanolamine (15.0 g, 150). and4-(2-piperidin-1-yl-ethoxy)-benzyl chloride (5.9 g, 20 mmol). Yield 5.5g, (85%); Brown semi-solid; MS: 323 (M+H)⁺.

Bis-(2-chloro-ethyl)-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-amine wasprepared according to the general method as outlined in example 83.Starting from2-[(2-Hydroxy-ethyl)-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-amine (3.22 g,10 mmol). Yield 4.0 g (92%); brown semi-solid; MS: 361.1 (M+H)⁺.

4-(4Methoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method asoutlined in example 83. Starting from from 4-(methoxy-benzenesulfonyl)acetic acid ethyl ester (5.0 g, 20 mmol) andBis-(2-chloro-ethyl)-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-amine (8.6 g,20 mmol). Yield 6.0 g (55%); brown oil; MS: 545.7 (M+H)⁺.

4(4-Methoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylicacid was prepared starting from4-(4-Methoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylicacid ethyl ester (5.4 g, 10 mmol) dissolved in THF:methanol 3:1 and 10 NNaOH (40 ml). The resulting reaction mixture was worked up as outlinedin example 83. Yield 4.0 g (77%); off white powder; mp 174° C.; MS:517.6 (M+H)⁺.

Starting from4-(4Methoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylicacid (3.5 g, 6.78 mmol) and following the procedure as outlined inexample 83 , 1.8 g of4-(4-Methoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylicacid hydroxy amide was isolated as an pale yellow solid. Yield 49%; mp114° C. (HCl); MS: 532 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ1.4-1.6 (m,4H), 1.9 (m, 2H), 2.3 (m, 2H), 2.8 (m, 2H), 3.4 (m, 4H), 3.9 (s, 3H),4.2 (m, 1H), 6.9-7.8 (m, 8H), 9.1 (s, 1H), 10.8 (bs, 1H).

EXAMPLE 110 N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-propionamide

Step A:Coupling of 2-bromo-propionic acid to hydroxylamine resin.

4-O-Methylhydroxylamine-phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin¹(2 g, 1.1 meq/g) was placed in a peptide synthesis vessel (ChemglassInc. Part Number CG-1866) and suspended in DMF (20 mL). 2-Bromopropionicacid (0.6 mL, 3.0 eq.) 1-hydroxybenzotriazole hydrate (HOBt, 1.8 g, 6.0eq.) and 1,3-diisopropylcarbodiimide (DIC, 1.4 mL, 4.0 eq.) were added.The reaction was shaken on an orbital shaker at room temperature for2-16 hours. The reaction was filtered and washed with DMF (3×20 mL). Asample of resin was removed and subjected to the Kaiser test. If thetest showed the presence of free amine (resin turned blue) the couplingdescribed above was repeated, otherwise the resin was washed with DCM(3×20 mL), MeOH (2×20 mL), and DCM (2×20 mL). (A wash consisted ofaddition of the solvent and agitation either by nitrogen bubbling orshaking on the orbital shaker for 1-5 minutes, then filtration undervacuum). The resin was dried in vacuo at room temperature. A sample ofresin (5-20 mg) was subjected to cleavage with DCM (0.5 mL) and TFA (0.5mL) for 1 hour at room temperature. The reaction was filtered and theresin washed with DCl (1×1 mL). The filtrate and the washing werecombined and concentrated in vacuo on a Savant SpeedVac Plus. Methanol(1 mL) was added and the mixture concentrated. The product was thencharacterized by H¹NMR, (DMSO d-6) δ4.54 (q, 1H), 1.83 (d, 3H).

Step B:Displacement of bromide with 4-methoxybenzenethiol.

The N-Hydroxy-2-bromo-propionamide resin prepared in Step A (0.35 g, 1.1meq/g) was placed in a 20 mL scintillation vial and suspended in THF (2mL). 4-Methoxybenzenethiol (0.23 mL, 5.0 eq.), sodium iodide (288 mg,5.0 eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.17 mL, 3.0 eq.)were added. The reaction was shaken at room temperature for 12-16 hours.The reaction mixture was poured into a polypropylene syringe barrelfitted with a polypropylene frit, filtered and washed with DMF (2×2 mL),DMF:water 9:1 (2×2 mL), DMF (2 mL), MeOH (2×2 mL), and DCM (2×2 mL). Theresin was dried in vacuo at room temperature.

Step C:Oxidation of sulfide to sulfoxide.

N-Hydroxy-2-(4-methoxy-benzenesulfanyl)-propionamide resin prepared inStep B (175 mg, 1.1 meq/g) was suspended in DCM (3.0 mL) and 70%tert-butylhydroperoxide (1.0 mL) and benzenesulfonic acid (50 mg) wereadded. The reaction mixture was shaken on an orbital shaker at roomtemperature for 12-24 hours. The reaction was filtered and washed withDCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2 mL). The resinwas dried in vacuo at room temperature.

Step D:Oxidation of sulfide to sulfone.

N-Hydroxy-2-(4-methoxy-benzenesulfanyl)-propionamide resin prepared inStep B (175 mg, 1.1 meq/g) was suspended in DCM (3.0 mL) and mCPBA (180mg) was added. The reaction mixture was shaken on an orbital shaker atroom temperature for 12-24 hours. The reaction was filtered and washedwith DCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2 mL). Theresin was dried in vacuo at room temperature.

Step E: Cleavage of N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-propionamidefrom resin.

The N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-propionamide resin preparedin Step D (73 mg, 1.2 meq/g) was suspended in DCM (1.0 mL) and TFA (1.0ml) was added. The reaction was shaken for 1 hour at room temperature.The reaction was filtered and the resin washed with DCM (2×1 mL). Thefiltrate and the washing were combined and concentrated to dryness on aSavant SpeedVac Plus. Methanol (1 mL) was added and the mixtureconcentrated. 84% @ 215 nm; ¹H NMR (DMSO d-6) δ10.75 (brs, 1 H), 7.95(brs, 1H), 7.71 (dd, 2H), 7.16 (dd, 2H), 3.87 (s, 3H), 3.83 (q, 1H),1.26 (d, 3H).

The hydroxamic acids of Examples 111-113 are synthesized usingappropriate starting materials and following the steps in example 110.

EXAMPLE 111 N-Hydroxy-2-(4-methoxy-benzenesulfanyl)-propionamide. 72% @215 nm

N-Hydroxy-2-(4-methoxy-benzenesulfinyl)-propionamide. 76% @ 215 nm; ¹HNMR (DMSO d-6) δ10.90 & 10.60 (brs, 1H), 7.95 (brs, 1H) 7.61 & 7.52 (dd,2H), 7.15 & 7.10 (dd, 2 H), 3.83 & 3.82 (s, 3H), 3.42 & 3.28 (q 1H),1.23 & 0.97 (d, 3H).

EXAMPLE 112 N-Hydroxy-2-(3-methyl-butane-1-sulfanyl)-propionamide. 74% @215 nm

N-Hydroxy-2-(3-methyl-butane-1-sulfinyl)-propionamide. ¹H NMR (DMSO d-6)67 10.8 (brs 1H), 7.95 (brs, 1H), 3.45 & 3.31 (q, 1H), 2.71-2.50 (m,2H), 1.71-1.46 (m, 3H), 1.33 & 1.25 (d, 3H), 0.94-0.82 (m, 6H)

EXAMPLE 113 N-Hydroxy-2-(3-methyl-butane-1-sulfonyl)-propionamide. 84% @215 nm EXAMPLE 114N-hydroxy-3-methyl-2-(naphthalen-2-ylsulfanyl)-butyramide

Step A:Coupling of 2-bromo-3-methyl-butyric acid to hydroxylamine resin.

4-O-Methylhydroxylamine-phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin¹(5 g, 1.1 meq/g) was placed in a peptide synthesis vessel and suspendedin DMF (40 mL). 2-Bromo-3-methyl-butyric acid (9.96 g, 10.0 eq.) and DIC(9.04 mL, 10.5 eq.) were added. The reaction was shaken on an orbitalshaker at room temperature for 2-16 hours. The reaction was filtered andwashed with DMF (3×20 mL). A sample of resin was removed and subjectedto the Kaiser test. If the test showed the presence of free amine (resinturned blue) the coupling described above was repeated, otherwise theresin was washed with DCM (3×20 mL), MeOH (2×20 mL), and DCM (2×20 mL).The resin was dried in vacuo at room temperature.

Step B:Displacement of bromide with 2-naphthalenethiol.

The 2-bromo hydroxymate resin prepared in Step A (0.15 g, 1.1 meq/g) wasplaced in a 20 mL scintillation vial and suspended in THF (2 mL).2-Naphthalenethiol (138 mg, 5.0 eq.), sodium iodide (129 mg, 5.0 eq.)and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.078 mL, 3.0 eq.) wereadded. The reaction was shaken at room temperature for 12-16 hours. Thereaction mixture was poured into a polypropylene syringe barrel fittedwith a polypropylene frit, filtered and washed with DMF (2×2 mL),DMF:water 9:1 (2×2 mL), DMF (2 mL), MeOH (2×2 mL), and DCM (2×2 mL). Theresin was dried in vacuo at room temperature.

Step C:Oxidation of sulfide to sulfoxide.

2-(2-Naphthalenesulfanyl)-N-hydroxypropionamide resin prepared in Step B(175 mg, 1.1 meq/g) was suspended in DCM (3.0 mL) and 70%tert-butylhydroperoxide (1.0 mL) benzenesulfonic acid (50 mg) wereadded. The reaction mixture was shaken on an orbital shaker at roomtemperature for 12-24 hours. The reaction was filtered and washed withDCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2 mL). The resinwas dried in vacuo at room temperature.

Step D: Oxidation of sulfide to sulfone.

2-(2-Naphthalenesulfanyl)-N-hydroxypropionamide resin prepared in Step B(175 mg, 1.1 meq/g) was suspended in DCM (3.0 mL) and mCPBA (180 mg) wasadded. The reaction mixture was shaken on an orbital shaker at roomtemperature for 12-24 hours. The reaction was filtered and washed withDCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2 mL). The resinwas dried in vacuo at room temperature.

Step E: Cleavage ofN-Hydroxy-3-methyl-2-(naphthalen-2-ylsulfanyl)-butyramide from resin.

The 2-(2-Naphthalenesulfanyl)-N-hydroxypropionamide resin prepared inStep B (73 mg, 1.2 meq/g) was suspended in DCN (1.0 mL) and TFA (1.0 mL)was added. The reaction was shaken for 1 hour at room temperature. Thereaction was filtered and the resin washed with DCM (2×1 mL). Thefiltrate and the washing were combined and concentrated to dryness on aSavant SpeedVac Plus. Methanol (1 mL) was added and the mixtureconcentrated. 83% @ 215 nm; LCMS (API-electrospray) m/z 276 (M+H)⁺; ¹HNMR (DMSO d-6) δ10.7 (brs, 1H), 7.91 (brs, 1H), 7.91-7.81 (m, 4H),7.55-7.45 (m, 3H), 3.41 (d, 1H), 2.09-1.97 (m, 1H), 1.05 (d, 3H), 0.97(d, 3H).

The hydroxamic acids of Examples 115-118 are synthesized usingappropriate starting materials and following the steps in example 114:

EXAMPLE 115 N-Hydroxy-3-methyl-2-(naphthalen-2-ylsulfinyl)-butyramide.67% @ 215 nm EXAMPLE 116N-Hydroxy-3-methyl-2-(naphthalen-2-ylsulfonyl)-butyramide. 97% @ 215 nm;LCMS (API-electrospray) m/z 308 (M+H)⁺ EXAMPLE 117N-Hydroxy-3-methyl-2-phenethylsulfinyl-butyramide. 93% @ 215 nm; LCMS(API-electrospray) m/z 254 (M+H)⁺ EXAMPLE 118N-Hydroxy-3-methyl-2-phenethylsulfonyl-butyramide. 97% @ 215 nm; LCMS(API-electrospray) m/z 286 (M+H)⁺ EXAMPLE 119(1-Hydroxycarbamoyl-propane-1-sulfanyl)-acetic acid methyl ester

Step A:Coupling of 2-bromobutyric acid to hydroxylamine resin.4O-Methylhydroxylamine-phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin¹(5 g, 1.1 meq/g) was placed in a peptide synthesis vessel and suspendedin DMF (40 mL). 2-Bromobutyric acid (3.0 g, 3.0 eq.) HOBt (4.86 g, 6.0eq.) and DIC (3.75 mL, 4.0 eq.) were added. The reaction was shaken onan orbital shaker at room temperature for 2-16 hours. The reaction wasfiltered and washed with DMF (3×20 mL). A sample of resin was removedand subjected to the Kaiser test. If the test showed the presence offree amine (resin turned blue) the coupling described above wasrepeated, otherwise the resin was washed with DCM (3×20 mL), MeOH (2×20mL), and DCM (2×20 mL). The resin was dried in vacuo at roomtemperature.

Step B:Displacement of bromide with methyl thioalycolate.

The 2-bromo hydroxymate resin prepared in Step A (0.45 g, 1.1 meq/g) wasplaced in a 20 mL scintillation vial and suspended in THF (2 mL). Methylthioglycolate (286 mg, 5.0 eq.), sodium iodide (404 mg, 5.0 eq.) and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.24 mL, 3.0 eq.) were added.The reaction was shaken at room temperature for 12-16 hours. Thereaction mixture was poured into a polypropylene syringe barrel fittedwith a polypropylene frit, filtered and washed with DMF (2×2 mL),DMF:water 9:1 (2×2 mL), DMF (2 mL), MeOH (2×2 mL), and DCM (2×2 mL). Theresin was dried in vacuo at room temperature.

Step C:Oxidation of sulfide to sulfoxide.

(1-Hydroxycarbamoyl-propane-1-sulfanyl)-acetic acid methyl ester resinprepared in Step B (150 mg, 1.1 meq/g) was suspended in DCM (3.0 mL) and70% tert-butylhydroperoxide (1.0 mL) benzenesulfonic acid (50 mg) wereadded. The reaction mixture was shaken on an orbital shaker at roomtemperature for 12-24 hours. The reaction was filtered and washed withDCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2 mL). The resinwas dried in vacuo at room temperature.

Step D:Oxidation of sulfide to sulfone.

(1-Hydroxycarbamoyl-propane-1-sulfanyl)-acetic acid methyl ester resinprepared in Step B (150 mg, 1.1 meq/g) was suspended in DCM (3.0 mL) andmCPBA (180 mg,) was added. The reaction mixture was shaken on an orbitalshaker at room temperature for 12-24 hours. The reaction was filteredand washed with DCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2mL). The resin was dried in vacuo at room temperature.

Step E:Cleavage of (1-Hydroxycarbamoyl-propane-1-sulfanyl)-acetic acidmethyl ester from resin

The (1-Hydroxycarbamoyl-propane-1-sulfanyl)-acetic acid methyl esterresin prepared in Step B (150 mg, 1.2 meq/g) was suspended in DCM (1.0mL) and TFA (1.0 mL) was added. The reaction was shaken for 1 hour atroom temperature. The reaction was filtered and the resin washed withDCM (2×1 mL). The filtrate and the washing were combined andconcentrated to dryness on a Savant SpeedVac Plus. Methanol (1 mL) wasadded and the mixture concentrated. LCMS (API-electrospray) m/z 228(M+Na)⁺.

The hydroxamic acids of Examples 120-124 are synthesized usingappropriate starting materials and following the steps in example 119.

EXAMPLE 120 (1-Hydroxycarbamoyl-propane-1-sulfonyl)-acetic acidhydroxyamide. LCMS (API-electrospray) m/z 224 (M+H)⁺ EXAMPLE 121(1-Hydroxycarbamoyl-propane-1-sulfinyl)-acetic acid hydroxy amide. 100%@ 220 nm; LCMS (API-electrospray) m/z 240 (M+H)⁺ EXAMPLE 122(1-Hydroxycarbamoyl-propane-1-sulfanyl)-propionic acid hydroxyamide

¹H NMR (DMSO d-6) δ10.7 (brs, 1H), 4.03 (t, 2H), 2.95 (q, 1H), 2.75-2.70(m, 1H), 2.60-2.54 (m, 1H), 1.74-1.66 (m, 2H), 1.58-1.50 (m, 4H), 1.32(sextet, 2H), 0.88 (t, 3 H), 0.85 (t, 3H); LCMS (API-electrospray) M/z264 (M+H)⁺.

EXAMPLE 123 (1-Hydroxycarbamoyl-propane-1-sulfinyl)-propionic acidhydroxyamide. 83% @ 220 nm; LCMS (API-electrospray) m/z 280 (M+H)⁺EXAMPLE 124 (1-Hydroxycarbamoyl-propane-1-sulfonyl)-propionic acidhydroxyamide 100% @ 220 nm EXAMPLE 1252-(4-Hydroxybenzenesulfanyl)-N-hydroxy-3-phenyl-propionamide

Step A:Coupling of 2-bromo-3-phenyl-propionic acid to hydroxylamineresin.

4O-Methylhydroxylamine-phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin¹(5 g, 1.2 meq/g) was placed in a peptide synthesis vessel and suspendedin DMF (40 mL). 2-Bromo-3-phenyl-propionic acid (3.5 g, 3.0 eq.) HOBt(4.4 g, 6.0 eq.) and DIC (3.4 mL, 4.0 eq.) were added. The reaction wasshaken on an orbital shaker at room temperature for 2-16 hours. Thereaction was filtered and washed with DMF (3×20 mL). A sample of resinwas removed and subjected to the Kaiser test. If the test showed thepresence of free amine (resin turned blue) the coupling described abovewas repeated, otherwise the resin was washed with DCM (3×20 mL), MeOH(2×20 mL), and DCM (2×20 mL). The resin was dried in vacuo at roomtemperature.

Step B:Displacement of bromide with 4hydroxythiophenol.

The 2-bromo hydroxymate resin prepared in Step A (0.33 g, 1.2 meq/g) wasplaced in a 20 mL scintillation vial and suspended in THF (2 mL).4-Hydroxythiophenol (250 mg, 5.0 eq.), sodium iodide (297 mg, 5.0 eq.)and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.18 mL, 3.0 eq.) wereadded. The reaction was shaken at room temperature for 12-16 hours. Thereaction mixture was poured into a polypropylene syringe barrel fittedwith a polypropylene frit, filtered and washed with DMF (2×2 mL),DMF:water 9:1 (2×2 mL), DMF (2 mL), MeOH (2×2 mL), and DCM (2×2 mL). Theresin was dried in vacuo at room temperature.

Step C:Oxidation of sulfide to sulfoxide.

2-(4-Hydroxybenzenesulfanyl)-N-hydroxy-3-phenyl-propionamide resinprepared in Step B (110 mg, 1.1 meq/g) was suspended in DCM (3.0 mL) and70% tert-butylhydroperoxide (0.73 mL) benzenesulfonic acid (36 mg) wereadded. The reaction mixture was shaken on an orbital shaker at roomtemperature for 12-24 hours. The reaction was filtered and washed withDCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2 mL). The resinwas dried in vacuo at room temperature.

Step D:Oxidation of sulfide to sulfone.

2-(4-Hydroxybenzenesulfanyl)-N-hydroxy-3-phenyl-propionamide resinprepared in Step B (110 mg, 1.1 meq/g) was suspended in DCM (3.0 mL) andmCPBA (132 mg) was added. The reaction mixture was shaken on an orbitalshaker at room temperature for 12-24 hours. The reaction was filteredand washed with DCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2mL). The resin was dried in vacuo at room temperature.

Step E:Cleavage of2-(4-Hydroxybenzenesulfanyl)-N-hydroxy-3-phenyl-propionamide from resin.

The 2-(4-Hydroxybenzenesulfanyl)-N-hydroxy-3-phenyl-propionamide resinprepared in Step B (110 mg, 1.2 meq/g) was suspended in DCM (1.0 mL) andTFA (1.0 mL) was added. The reaction was shaken for 1 hour at roomtemperature. The reaction was filtered and the resin washed with DCM(2×1 mL). The filtrate and the washing were combined and concentrated todryness on a Savant SpeedVac Plus. Methanol (1 mL) was added and themixture concentrated. 84% @ 215 nm; ¹H NMR (DMSO d-6) δ10.41 (brs, 1H),7.95 (brs (1H), 7.30-7.15 (m, 5H), 7.10 (dd, 2H), 6.75 (dd, 2H), 3.53(q, 1H), 3.05 (dd, 1H), 2.79 (dd, 1H).

The hydroxamic acids of Examples 126-130 are synthesized usingappropriate starting materials and following the steps in example 125.

EXAMPLE 126 2-(4Hydroxybenzenesulfinyl)-N-hydroxy-3-phenyl-propionamide.73% @ 215 nm EXAMPLE 1272-(4-Hydroxybenzenesulfonyl)-N-hydroxy-3-phenyl-propionamide. 77% @ 215nm; ¹H NMR (DMSO d-6) δ10.50 (brs, 1H), 7.95 (brs, 1H), 7.68-7.57 (m,2H), 7.28-7.17 (m, 3H), 7.08-7.98 (m, 2H), 6.95-6.87 (m, 2H), 3.96 (t, 1H), 3.02 (d, 2H) EXAMPLE 1282-(4-Acetylamino-benzenesulfanyl)-N-hydroxy-3-phenyl-propionamide. 86% @215 nm; ¹H NMR (DMSO d-6) δ10.50 (brs, 1H), 10.03 (brs, 1H), 8.13 (brs,1H), 7.56-7.12 (m, 9H), 3.67 (q, 1H), 3.08 (dd, 1H), 2.84 (dd, 1H), 2.04(s, 3 H) EXAMPLE 1292-(4-Acetylamino-benzenesulfinyl)-N-hydroxy-3-phenyl-propionamide. 73% @215 nm EXAMPLE 1302-(4-Acetylamino-benzenesulfonyl)-N-hydroxy-3-phenyl-propionariide. 95%@ 215 nm EXAMPLE 1314-Hydroxycarbamoyl-4(4-methanesulfanyl-phenylsulfanyl)-butyric acidmethyl ester

Step A:Coupling of 2-bromo-5-methyl glutaric acid to hydroxylamineresin.

4-O-Methylhydroxylamine-phenoxymethylcopoly(styrene-1%-divinylbenzene)-resin¹(4.5 g, 1.2 meq/g) was placed in a peptide synthesis vessel andsuspended in DMF (40 mL). S-2-Bromo-5-methyl glutarate (3.87 g, 3.0 eq.)HOBt (4.4 g, 6.0 eq.) and DIC (3.4 mL, 4.0 eq.) were added. The reactionwas shaken on an orbital shaker at room temperature for 2-16 hours. Thereaction was filtered and washed with DME (3×20 mL). A sample of resinwas removed and subjected to the Kaiser test. If the test showed thepresence of free amine (resin turned blue) the coupling described abovewas repeated, otherwise the resin was washed with DCM (3×20 mL), MeOH(2×20 mL), and DCM (2×20 mL). The resin was dried in vacuo at roomtemperature.

Step B:Displacement of bromide with 4-hydroxythiophenol.

The 2-bromo hydroxymate resin prepared in Step A (0.22 g, 1.2 meq/g) wasplaced in a 20 mL scintillation vial and suspended in THF (2 mL).4-(Methylthio)thiophenol (206 mg, 5.0 eq.), sodium iodide (197 mg, 5.0eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.12 mL, 3.0 eq.) wereadded. The reaction was shaken at room temperature for 12-16 hours. Thereaction mixture was poured into a polypropylene syringe barrel fittedwith a polypropylene frit, filtered and washed with DMF (2×2 mL),DMF:water 9:1 (2×2 mL), DMF (2 mL), MeOH (2×2 mL), and DCM (2×2 mL). Theresin was dried in vacuo at room temperature.

Step C:Oxidation of sulfide to sulfoxide.

4Hydroxycarbamoyl-4-(4-methanesulfanyl-phenylsulfanyl)-butyric acidmethyl ester resin prepared in Step B (73 mg, 1.1 meq/l) was suspendedin DCM (1.5 mL) and 70% tert-butylhydroperoxide (0.49 mL)benzenesulfonic acid (24 mg) were added. The reaction mixture was shakenon an orbital shaker at room temperature for 12-24 hours. The reactionwas filtered and washed with DCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL),and DCM (2×2 mL). The resin was dried in vacuo at room temperature.

Step D:Oxidation of sulfide to sulfone.

4Hydroxycarbamoyl4(4-methanesulfanyl-phenylsulfanyl)-butric acid methylester resin prepared in Step B (73 mg, 1.1 meq/g) was suspended in DCM(1.5 mL) and mCPBA (87 mg) was added. The reaction mixture was shaken onan orbital shaker at room temperature for 12-24 hours. The reaction wasfiltered and washed with DCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), andDCM (2×2 mL). The resin was dried in vacuo at room temperature.

Step E: Cleavage of4-Hydroxycarbamoyl-4-(4methanesulfanyl-phenylsulfanyl)-butyric acidmethyl ester from resin.

The 4-Hydroxycarbamoyl4-(4methanesulfanyl-phenylsulfanyl)-butyric acidmethyl ester resin prepared in Step B (73 mg, 1.2 meq/g) was suspendedin DCM (1.0 mL) and TFA (1.0 mL) was added. The reaction was shaken for1 hour at room temperature. The reaction was filtered and the resinwashed with DCM (2×1 mL). The filtrate and the washing were combined andconcentrated to dryness on a Savant SpeedVac Plus. Methanol (1 mL) wasadded and the mixture concentrated. 77% @ 215 nm; LCMS(API-electrospray) m/z 316 (M+H)⁺.

The hydroxamic acids of Examples 132-139 are synthesized usingappropriate starting materials and following the steps in example 131.

EXAMPLE 132

4Hydroxycarbamoyl-4-(4-methanesulfinyl-phenylsulfinyl)-butyric acidhydroxyamide. 79% @ 215 mm; LCMS (API-electrospray) m/z 348 (M+H)⁺

EXAMPLE 1334Hydroxycarbamoyl4-(4-methanesulfonyl-phenylsulfonyl)-butyric acidhydroxyamide. 78% @ 215 nm; LCMS (API-electrospray) n/z 380 (M+H)⁺EXAMPLE 134 4-Hydroxycarbamoyl-4-(4-bromo-benzenesulfanyl)-butyric acidhydroxyamide. 93% @ 215 nm EXAMPLE 1354Hydroxycarbamoyl4-(4-bromo-benzenesulfinyl)-butyric acid hydroxyamide.80% @ 215 nm. EXAMPLE 1364-Hydroxycarbamoyl-4-(bromo-benzenesulfonyl)-butyric acid hydroxyamide.77% @ 215 nm EXAMPLE 1374-Hydroxycarbamoyl-4-(2-trifluoromethyl-benzenesulfanyl)-butric acidhydroxyamide. 93% @ 215 nm EXAMPLE 1384-Hydroxycarbamoyl-4-(2-trifluoromethyl-benzenesulfinyl)-butyric acidhydroxyamide. 72% @ 215 nm EXAMPLE 1394-Hydroxycarbamoyl-4-(2-trifluoromethyl-benzenesulfonyl)-butyric acidhydroxyamide. 90% @ 215 nm EXAMPLE 1402-(3-methoxy-benzenesulfanyl)decanoic acid hydroxamide

Step A:Coupling of 2-bromo-decanoic acid to hydroxyl amine resin.

4-O-Methylhydroxylamine-phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin¹(4.5 g, 1.2 meq/g) was placed in a peptide synthesis vessel andsuspended in DMF (40 mL). 2-Bromo-decanoic acid (4.07 g, 3.0 eq.) HOBt(4.4 g, 6.0 eq.) and DIC (3.4 mL, 4.0 eq.) were added. The reaction wasshaken on an orbital shaker at room temperature for 2-16 hours. Thereaction was filtered and washed with DMF (3×20 mL). A sample of resinwas removed and subjected to the Kaiser test. If the test showed thepresence of free amine (resin turned blue) the coupling described abovewas repeated, otherwise the resin was washed with DCM (3×20 mL), MeOH(2×20 mL), and DCM (2×20 mL). The resin was dried in vacuo at roomtemperature.

Step B:Displacement of bromide with 3-methoxy-benzenethiol.

The 2-bromo hydroxymate resin prepared in Step A (0.22 g, 1.2 meq/g) wasplaced in a 20 mL scintillation vial and suspended in THF (2 mL).3-Methoxy-benzenethiol (185 mg, 5.0 eq.), sodium iodide (197 mg, 5.0eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.12 mL, 3.0 eq.) wereadded. The reaction was shaken at room temperature for 12-16 hours. Thereaction mixture was poured into a polypropylene syringe barrel fittedwith a polypropylene frit, filtered and washed with DMF (2×2 mL),DMF:water 9:1 (2×2 mL), DMF (2 mL), MeOH (2×2 mL), and DCM (2×2 mL). Theresin was dried in vacuo at room temperature.

Step C:Oxidation of sulfide to sulfoxide.

2-(3-Methoxy-benzenesulfanyl)decanoic acid hydroxamide resin prepared inStep B (73 mg, 1.1 meq/g) was suspended in DCM (1.5 mL) and 70%tert-butylhydroperoxide (0.49 mL) benzenesulfonic acid (24 mg) wereadded. The reaction mixture was shaken on an orbital shaker at roomtemperature for 12-24 hours. The reaction was filtered and washed withDCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2 mL). The resinwas dried in vacuo at room temperature.

Step D:Oxidation of sulfide to sulfone.

2-(3-Methoxy-benzenesulfanyl)decanoic acid hydroxamide resin prepared inStep B (73 mg, 1.1 meq/g) was suspended in DCM (1.5 mL) and mCPBA (87mg) was added. The reaction mixture was shaken on an orbital shaker atroom temperature for 12-24 hours. The reaction was filtered and washedwith DCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2 mL). Theresin was dried in vacuo at room temperature.

Step E:Cleavage of 2-(3-methoxy-benzenesulfanyl)decanoic acidhydroxamide from resin.

The 2-(3-methoxy-benzenesulfanyl)decanoic acid hydroxamide resinprepared in Step B (73 mg, 1.2 meq/g) was suspended in DCM (1.0 mL) andTFA (1.0 mL) was added. The reaction was shaken for 1 hour at roomtemperature. The reaction was filtered and the resin washed with DCM(2×1 mL). The filtrate and the washing were combined and concentrated todryness on a Savant SpeedVac Plus. Methanol (1 mL) was added and themixture concentrated. 89% @ 215 nm. The hydroxamic acids of Examples141-145 are synthesized using appropriate starting materials andfollowing the steps in example 140.

EXAMPLE 141 2-(3-Methoxy-benzenesulfinyl)decanoic acid hydroxamide. 96%@ 215 nm EXAMPLE 142 2-(3-Methoxy-benzenesulfonyl)decanoic acidhydroxamide. 96% @ 215 nm EXAMPLE 1432-(4methanesulfanyl-benzenesulfanyl)decanoic acid hydroxamide. 85% @ 215nm; LCMS (API-electrospray) m/z 342 (M+H)⁺ EXAMPLE 1442-(4-methanesulfinyl-benzenesulfinyl)decanoic acid hydroxamide. 86% @215 nm; LCMS (API-electrospray) m/z 374 (M+H)⁺ EXAMPLE 1452-(4-methanesulfonyl-benzenesulfonyI)decanoic acid hydroxamide. 92% @215 nm EXAMPLE 1463-benzyloxy-N-hydroxy-2-(4-methanesulfanyl-benzenesulfanyl)-propionamide

Step A:Coupling of 2-bromo-3-benzyloxy propionic acid to hydroxylamineresin.4-O-Methylhydroxylamine-phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin¹(4.5 g, 1.2 meq/g) was placed in a peptide synthesis vessel andsuspended in DMF (40 mL). S-2-Bromo-3-benzyloxy-propionic acid (4.2 g,3.0 eq.) HOBT (4.4 g, 6.0 eq.) and DIC (3.4 mL, 4.0 eq.) were added. Thereaction was shaken on an orbital shaker at room temperature for 2-16hours. The reaction was filtered and washed with DMF (3×20 mL). A sampleof resin was removed and subjected to the Kaiser test. If the testshowed the presence of free amine (resin turned blue) the couplingdescribed above was repeated, otherwise the resin was washed with DCM(3×20 mL), MeOH (2×20 mL), and DCM (2×20 mL). The resin was dried invacuo at room temperature.

Step B:Displacement of bromide with 4-(methylthio)thiophenol.

The 2-bromo hydroxymate resin prepared in Step A (0.22 g, 1.2 meq/g) wasplaced in a 20 mL scintillation vial and suspended in THF (2 mL).4-(Methylthio)thiophenol (206 mg, 5.0 eq.), sodium iodide (197 mg, 5.0eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.12 mL, 3.0 eq.) wereadded. The reaction was shaken at room temperature for 12-16 hours. Thereaction mixture was poured into a polypropylene syringe barrel fittedwith a polypropylene frit, filtered and washed with DMF (2×2 mL),DMF:water 9:1 (2×2 mL), DMF (2 mL), MeOH (2×2 mL), and DCM (2×2 mL). Theresin was dried in vacuo at room temperature.

Step C:Oxidation of sulfide to sulfoxide.

3-Benzyloxy-N-hydroxy-2-(4-methanesulfanyl-benzenesulfanyl)-propionamideresin prepared in Step B (73 mg, 1.1 meq/g) was suspended in DCM (1.5mL) and 70% tert-butylhydroperoxide (0.49 mL) benzenesulfonic acid (24mg) were added. The reaction mixture was shaken on an orbital shaker atroom temperature for 12-24 hours. The reaction was filtered and washedwith DCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2 mL). Theresin was dried in vacuo at room temperature.

Step D:Oxidation of sulfide to sulfone.

3-Benzyloxy-N-hydroxy-2-(4-methanesulfanyl-benzenesulfanyl)-propionamideresin prepared in Step B (73 mg, 1.1 meq/g) was suspended in DCM (1.5mL) and mCPBA (87 mg) was added. The reaction mixture was shaken on anorbital shaker at room temperature for 12-24 hours. The reaction wasfiltered and washed with DCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), andDCM (2×2 mL). The resin was dried in vacuo at room temperature.

Step E:Cleavage of3-benzyloxy-N-hydroxy-2-(4-methanesulfanyl-benzenesulfanyl)-propionamidefrom resin.

The3-benzyloxy-N-hydroxy-2-(4-methanesulfanyl-benzenesulfanyl)-propionamideresin prepared in Step B (73 mg, 1.2 meq/g) was suspended in DCM (1.0mL) and TFA (1.0 mL) was added. The reaction was shaken for 1 hour atroom temperature. The reaction was filtered and the resin washed withDCM (2×1 mL). The filtrate and the washing were combined andconcentrated to dryness on a Savant SpeedVac Plus. Methanol (1 mL) wasadded and the mixture concentrated. 76% @ 215 nm; LCMS(API-electrospray) m/z 350 (M+H)⁺.

The hydroxamic acids of Examples 147-151 are synthesized usingappropriate starting materials and following the steps in example 146.

EXAMPLE 1473-Benzyloxy-N-hydroxy-2-(4methanesulfinyl-benzenesulfinyl)-propionamide.70% @ 215 nm; LCMS (API-electrospray) m/z 382 (M+H)⁺ EXAMPLE 1483-Benzyloxy-N-hydroxy-2-(4-methanesulfonyl-benzenesulfonyl)-propionamide.63% @ 215 nm; LCMS (API-electrospray) m/z 414 (M+H)⁺ EXAMPLE 1493-Benzyloxy-N-hydroxy-2-(2-chloro-benzylsulfanyl)-propionamide. 90% @215 nm EXAMPLE 1503-Benzyloxy-N-hydroxy-2-(2-chloro-benzylsulfinyl)-propionamide. 70% @215 nm EXAMPLE 1513-Benzyloxy-N-hydroxy-2-(2-chloro-benzylsulfonyl)-propionamide. 72% @215 nm EXAMPLE 1522-(2-bromo-benzenesulfanyl)-N-hydroxy-3-(3H-imidazol-4-yl)-propionamide

Step A:Coupling of 2-bromo-3-(3H-imidazol-4-yl)-propionic acid tohydroxylamine resin.

4-O-Methylhydroxylamine-phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin¹(4.5 g, 1.2 meq/g) was placed in a peptide synthesis vessel andsuspended in DMF (40 mL). S-2-Bromo-3-(3H-imidazol4yl)-propionic acid(3.55 g, 3.0 eq.) HOBt (4.4 g, 6.0 eq.) and DIC (3.4 mL, 4.0 eq.) wereadded. The reaction was shaken on an orbital shaker at room temperaturefor 2-16 hours. The reaction was filtered and washed with DMF (3×20 mL).A sample of resin was removed and subjected to the Kaiser test. If thetest showed the presence of free amine (resin turned blue) the couplingdescribed above was repeated, otherwise the resin was washed with DCM(3×20 mL), MeOH (2×20 mL), and DCM (2×20 mL). The resin was dried invacuo at room temperature.

Step B:Displacement of bromide with 2-bromothiophenol.

The 2-bromo hydroxymate resin prepared in Step A (0.22 g, 1.2 meq/g) wasplaced in a 20 mL scintillation vial and suspended in THF (2 mL).2-Bromothiophenol (249 mg, 5.0 eq.), sodium iodide (197 mg, 5.0 eq.) and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.12 mL, 3.0 eq.) were added.The reaction was shaken at room temperature for 12-16 hours. Thereaction mixture was poured into a polypropylene syringe barrel fittedwith a polypropylene frit, filtered and washed with DMF (2×2 mL),DMF:water 9:1 (2×2 mL), DMF (2 mL), MeOH (2×2 mL), and DCM (2×2 mL). Theresin was dried in vacuo at room temperature.

Step C:Oxidation of sulfide to sulfoxide.

2-(2-Bromo-benzenesulfanyl)-N-hydroxy-3-(3H-imidazol4 yl)-propionamideresin prepared in Step B (73 mg, 1.1 meq/g) was suspended in DCM (1.5mL) and 70% tert-butylhydroperoxide (0.49 mL) benzenesulfonic acid (24mg) were added. The reaction mixture was shaken on an orbital shaker atroom temperature for 12-24 hours. The reaction was filtered and washedwith DCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2 mL). Theresin was dried in vacuo at room temperature.

Step D:Oxidation of sulfide to sulfone.

2-(2-Bromo-benzenesulfanyl)-N-hydroxy-3-(3H-imidazol4-yl)-propionamideresin prepared in Step B (73 mg, 1.1 meq/g) was suspended in DCM (1.5mL) and mCPBA (87 mg) was added. The reaction mixture was shaken on anorbital shaker at room temperature for 12-24 hours. The reaction wasfiltered and washed with DCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), andDCM (2×2 mL). The resin was dried in vacuo at room temperature.

Step E: Cleavage of2-(2-bromo-benzenesulfanyl)-N-hydroxy-3-(3HH-imidazol4-yl)-propionamidefrom resin.

The2-(2-bromo-benzenesulfanyl)-N-hydroxy-3-(3H-imidazol-4-yl)-propionamideresin prepared in Step B (73 mg, 1.2 meq/g) was suspended in DCM (1.0mL) and TFA (1.0 mL) was added. The reaction was shaken for I hour atroom temperature. The reaction was filtered and the resin washed withDCM (2×1 mL). The filtrate and the washing were combined andconcentrated to dryness on a Savant SpeedVac Plus. Methanol (1 mL) wasadded and the mixture concentrated. 86% @ 215 nm.

The hydroxamic acids of Examples 153-154 are synthesized usingappropriate starting materials and following the steps in example 152.

EXAMPLE 1532-(4-bromo-benzenesulfinyl)-N-hydroxy-3-(3H-imidazol-4-yl)-propionamide.69% @ 215 nm EXAMPLE 1542-(4-chloro-benzenesulfonyl)-N-hydroxy-3-(3H-imidazol-4-yl)-propionamideEXAMPLE 155 2-(3-fluorophenylsulfanyl)-5-guanidino-pentanoic acidhydroxyamide

Step A:Coupling of 2-bromo-5-guanidino-pentanic acid to hydroxylamineresin.

4O-Methylhydroxylamine-phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin¹(4.5 g, 1.2 meq/g) was placed in a peptide synthesis vessel andsuspended in DMF (40 mL). S-2-Bromo-5-guanidino-pentanic acid (3.85 g,3.0 eq.) HOBt (4.4 g, 6.0 eq.) and DIC (3.4 mL, 4.0 eq.) were added. Thereaction was shaken on an orbital shaker at room temperature for 2-16hours. The reaction was filtered and washed with DMF (3×20 mL). A sampleof resin was removed and subjected to the Kaiser test. If the testshowed the presence of free amine (resin turned blue) the couplingdescribed above was repeated, otherwise the resin was washed with DCM(3×20 mL), NeOH (2×20 mL), and DCM (2×20 mL). The resin was dried invacuo at room temperature.

Step B:Displacement of bromide with 3-fluorothiophenol.

The 2-bromo hydroxymate resin prepared in Step A (0.22 g, 1.2 meq/g) wasplaced in a 20 mL scintillation vial and suspended in THF (2 mL).3-Fluorothiophenol (169 mg, 5.0 eq.), sodium iodide (197 mg, 5.0 eq.)and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.12 mL, 3.0 eq.) wereadded. The reaction was shaken at room temperature for 12-16 hours. Thereaction mixture was poured into a polypropylene syringe barrel fittedwith a polypropylene frit, filtered and washed with DMF (2×2 mL),DMF:water 9:1 (2×2 mL), DMF (2 mL), MeOH (2×2 mL), and DCM (2×2 mL). Theresin was dried in vacuo at room temperature.

Step C:Oxidation of sulfide to sulfoxide.

2-(3-Fluorophenylsulfanyl)-5-guanidino-pentanoic acid hydroxyamide resinprepared in Step B (73 mg, 1.1 meq/g) was suspended in DCM (1.5 mL) and70% tert-butylhydroperoxide (0.49 mL) benzenesulfonic acid (24 mg) wereadded. The reaction mixture was shaken on an orbital shaker at roomtemperature for 12-24 hours. The reaction was filtered and washed withDCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2 mL). The resinwas dried in vacuo at room temperature.

Step D: Oxidation of sulfide to sulfone.

2-(3-Fluorophenylsulfanyl)-5-guanidino-pentanoic acid hydroxyamide resinprepared in Step B (73 mg, 1.1 meq/g) was suspended in DCM (1.5 mL) andmCPBA (87 mg) was added. The reaction mixture was shaken on an orbitalshaker at room temperature for 12-24 hours. The reaction was filteredand washed with DCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2mL). The resin was dried in vacuo at room temperature.

Step E: Cleavage of 2-(3-fluorophenylsulfanyl)-5-guanidino-pentanoicacid hydroxyamide from resin.

The 2-(3-fluorophenylsulfanyl)-5-guanidino-pentanoic acid hydroxyamideresin prepared in Step B (73 mg, 1.2 meq/g) was suspended in DCM (1.0mL) and TFA (1.0 mL) was added. The reaction was shaken for 1 hour atroom temperature. The reaction was filtered and the resin washed withDCM (2×1 mL). The filtrate and the washing were combined andconcentrated to dryness on a Savant SpeedVac Plus. Methanol (1 mL) wasadded and the mixture concentrated. 93% @ 215 nm.

The hydroxamic acids of Examples 156-159 are synthesized usingappropriate starting materials and following the steps in example 155:

EXAMPLE 156 2-(3-Fluorophenylsulfinyl)-5-guanidino-pentanoic acidhydroxyamide. 80% @ 220 nm; LCMS (API-electrospray) m/z 317 (M+H)⁺EXAMPLE 157 2-(2-Bromosulfanyl)-5-guanidino-pentanoic acid hydroxyamide.92% @ 220 nm; ¹H NMR (DMSO d-6) δ10.90 (brs, 2H), 10.41 (brs, 1H), 7.95(brs, 1H), 7.66-7.14 (m, 5H), 3.72 (q, 1H), 3.13 (q, 2H), 1.90-1.66 (m,2H), 1.58-1.43 (2H). EXAMPLE 1582-(2-Bromosulfinyl)-5-guanidino-pentanoic acid hydroxyamide. 79% @ 220nm; LCMS (API-electrospray) m/z 379 (M+H)⁺ EXAMPLE 1592-(2-Bromosulfonyl)-5-guanidino-pentanoic acid hydroxyamide. ¹H NMR(DMSO d-6) δ8.03-7.45 (m, 5H), 4.52 (q, 1H), 3.16 (q, 2H), 2.07-1.90 (m,2H), 1.66-1.59 (2H) EXAMPLE 160 2-(2,5-dichlorobenzenesulfanyl)-octanoicacid hydroxyamide

Step A:Coupling of 2-bromo-octanoic acid to hydroxyl amine resin.

4-O-Methylhydroxylamine-phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin¹(10.0 g, 1.2 meq/g) was placed in a peptide synthesis vessel andsuspended in DMF (80 mL). 2-Bromo-octanoic acid (8.4 g, 3.0 eq.) HOBt(8.8 g, 6.0 eq.) and DIC (7.2 mL, 4.0 eq.) were added. The reaction wasshaken on an orbital shaker at room temperature for 2-16 hours. Thereaction was filtered and washed with DMF (3×20 mL). A sample of resinwas removed and subjected to the Kaiser test. If the test showed thepresence of free amine (resin turned blue) the coupling described abovewas repeated, otherwise the resin was washed with DCM (3×20 mL), MeOH(2×20 mL), and DCM (2×20 mL). The resin was dried in vacuo at roomtemperature.

Step B:Displacement of bromide with 2,5-dichlorothiophenol.

The 2-bromo hydroxymate resin prepared in Step A (0.45 g, 1.2 meq/g) wasplaced in a 20 mL scintillation vial and suspended in THF (6 mL).2,5-Dichlorothiophenol (483 mg, 5.0 eq.), sodium iodide (404 mg, 5.0eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.24 mL, 3.0 eq.) wereadded. The reaction was shaken at room temperature for 12-16 hours. Thereaction mixture was poured into a polypropylene syringe barrel fittedwith a polypropylene frit, filtered and washed with DNF (2×2 mL),DMF:water 9:1 (2×2 mL), DMF (2 mL), MeOH (2×2 mL), and DCM (2×2 mL). Theresin was dried in vacuo at room temperature.

Step C:Oxidation of sulfide to sulfoxide.

2-(2,5-Dichlorobenzenesulfanyl)-octanoic acid hydroxyamide resinprepared in Step B (150 mg, 1.1 meq/g) was suspended in DCM (3.0 mL) and70% tert-butylhydroperoxide (1.0 mL) benzenesulfonic acid (50 mg) wereadded. The reaction mixture was shaken on an orbital shaker at roomtemperature for 12-24 hours. The reaction was filtered and washed withDCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2 mL). The resinwas dried in vacuo at room temperature.

Step D:Oxidation of sulfide to sulfone.

2-(2,5-Dichlorobenzenesulfanyl)-octanoic acid hydroxyamide resinprepared in Step B (150 mg, 1.1 meq,g) was suspended in DCM (3.0 mL) andmCPBA (180 mg) was added. The reaction mixture was shaken on an orbitalshaker at room temperature for 12-24 hours. The reaction was filteredand washed with DCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2mL). The resin was dried in vacuo at room temperature.

Step E:Cleavage of 2-(2,5-dichlorobenzenesulfanyl)-octanoic acidhydroxyamide from resin.

The 2-(2,5-dichlorobenzenesulfanyl)-octanoic acid hydroxyamide resinprepared in Step B (73 mg, 1.2 meq/g) was suspended in DCM (1.0 mL) andTFA (1.0 mL) was added. The reaction was shaken for 1 hour at roomtemperature. The reaction was filtered and the resin washed with DCM(2×1 mL). The filtrate and the washing were combined and concentrated todryness on a Savant SpeedVac Plus. Methanol (1 mL) was added and themixture concentrated. 92% @ 215 nm; ¹H NMR (DMSO d-6) δ10.96 (brs, 1H),9.26 (brs, 1H), 7.93-7.76 (m, 3H), 4.07 (q, 1H), 2.04-1.85 (m, 1H),1.78-1.64 (m, 1H), 1.32-1.09 (m, 8 H), 0.81 (t, 3H).

The hydroxamic acids of Examples 161-167 are synthesized usingappropriate starting materials and following the steps in example 160.

EXAMPLE 161 2-(2,5-Dichlorobenzenesulfonyl)-octanoic acid hydroxyamide.96% @ 215 nm EXAMPLE 162 2-(3-Methoxybenzenesulfanyl)-octanoic acidhydroxyamide 86% @ 220 nm; LCMS (API-electrospray) m/z 298 (M+H)⁺EXAMPLE 163 2-(3-Methoxybenzenesulfinyl)-octanoic acid hydroxyamide 96%@ 220 nm 5 EXAMPLE 164 2-(3-Methoxybenzenesulfonyl)-octanoic acidhydroxyamide 83% @ 220 nm EXAMPLE 1652-(3,4-Dimethoxybenzenesulfanyl)-octanoic acid hydroxyamide 87% @ 215nm; LCMS (API-electrospray) m/z 328 (M+H)⁺ EXAMPLE 1662-(3,4Dimethoxybenzenesulfinyl)-octanoic acid hydroxyamide 90% @ 215 nmEXAMPLE 167 2-(3,4-Dimethoxybenzenesulfonyl)-octanoic acid hydroxyamide87% @ 215 nm

The hydroxamic acid compounds of Examples 168-198 are synthesized usingappropriate staring materials and following the steps in example 160.The crude products are dissolved in DMSO:methanol (1:1, 2 mL) andpurified by reverse phase HPLC under the conditions described below:

Column: ODS-A, 20 mm×50 mm, 5 μm particle size (YMC, Inc. Wilmington,N.C.

Solvent Gradient Time Water Acetonitrile 0.0 95  5 25 min.  5 95 FlowRate: 15 mL/min.

EXAMPLE 168 2-(2-Benzimidazol-2-ylsulfanyl)-octanoic acid hydroxyamide81% @ 215 nm; LCMS (API-electrospray) m/z 308 (M+H)⁺ EXAMPLE 1692-(2-Benzooxazol-2-ylsulfanyl)-octanoic acid hydroxyamide 72% @ 215 rim;LCMS (API-electrospray) m/z 309 (M+H)⁺ EXAMPLE 1702-(2-Benzothiazol-2-ylsulganyl)-octanoic acid hydroxyamide 72% @ 215 nm;LCMS (API-electospray) m/z 325 (M+H)⁺ EXAMPLE1712-(2-Pyndine-2-sulfanyl)-octanoic acid hydroxyamide 76% @ 215 nm; LCMS(API-electrospray) m/z 269 (M+H)⁺ EXAMPLE 1722-(4Phenyl-thiazole-2-sulfanyl)-octanoic acid hydroxyamide 97% @ 215 nm;LCMS (API-electrospray) m/z 336 (M+H)⁺ EXAMPLE 1732-(2-Pyridin-2-yl-ethylsulfanyl)-octanoic acid hydroxyamide 84% @ 215nm; LCMS (API-electrospray) m/z 297 (M+H)⁺ EXAMPLE 1742-(2-Phenyl-5H-tetrazol-5-ylsulfanyl)-octanoic acid hydroxyamide 67% @215 nm; LCMS (API-electrospray) m/z 338 (M+H)⁺ EXAMPLE 1752-(2-Pyrazin-2-yl-ethylsulfanyl)-octanoic acid hydroxyamide 98% @ 215nm; LCMS (API-electrospray) m/z 298 (M+H)⁺ EXAMPLE 1762-(1-Methyl-1H-tetrazol-5-yl sulfanyl)-octanoic acid hydroxyamide 66% @215 nm; LCMS (API-electrospray) m/z 274 (M+H)⁺ EXAMPLE 1772-(2-Benzimidazol-2-ylsulfinyl)-octanoic acid hydroxyamide 81% 215 nmEXAMPLE 178 2-(2-Pyridine-2-sulfinyl)-octanoic acid hydroxyamide 76% @215 nm EXAMPLE 179 2-(4-Phenyl-thiazole-2-sulfinyl)-octanoic acidhydroxyamide 78% @ 215 nm EXAMPLE 1802-(2-Pyrazin-2-yl-ethylsulfinyl)-octanoic acid hydroxyamide 96% @ 215nm; LCMS (API-electrospray) m/z 314 (M+H)⁺ EXAMPLE 1812-(3-Oxy-1H-benzimidazole-2-sulfonyl)-octanoic acid hydroxyamide 63% @215 nm; LCMS (API-electrospray) m/z 356 (M+H)⁺ EXAMPLE 1822-(4Phenyl-thiazole-2-sulfonyl)-octanoic acid hydroxyamide 70% @ 215 nm;LCMS (API-electrospray) m/z 383 (M+H)⁺ EXAMPLE 1832-[2-(1-Oxy-pyridin-2-yl)-ethanesulfonyl]octanoic acid hydroxyamide 77%@ 215 nm; LCMS (API-electrospray) m/z 345 (M+H)⁺ EXAMPLE 1843-(1-Hydroxycarbamoyl-heptylsulfanyl)-benzoic acid hydroxyamide. 100% @220 nm; LCMS (API-electrospray) m/z 312 (M+H)⁺ EXAMPLE 1853-[4(1-Hydroxycarbamoyl-heptylsulfanyl)-phenyl-propionic acidhydroxyamide. 90% @ 220 nm; LCMS (API-electrospray) m/z 340 (M+H)⁺EXAMPLE 186 2-Thiazol-2-ylsulfanyl)-octanoic acid hydroxyamide. 75% @215 nm; LCMS (API-electrospray) m/z 275 (M+H)⁺ EXAMPLE 1872-(2,5-Dioxo-imidazolidin-4-ylmethylsulfanyl)-octanoic acidhydroxyamide. 98% @ 215 nm; LCMS (API-electrospray) m/z 304 (M+H)⁺EXAMPLE 188 3-(1-Hydroxycarbamoyl-heptylsulfinyl)-benzoicacidhydroxyamide. 84% @ 220 nm; LCMS (API-electrospray) m/z 328 (M+H)⁺EXAMPLE 189 3-[4-(1-Hydroxycarbamoyl-heptylsulfinyl)-phenyl]-propionicacid hydroxarmide. 78% @ 220 nm; LCMS (API-electrospray) m/z 356 (M+H)⁺EXAMPLE 190 2-(Quinoline-8-sulfinyl)-octanoic acid hydroxyamide. 87% @220 nm; LCMS (API-electrospray) m/z 335 (M+H)⁺ EXAMPLE 1912-(Naphthalen-2-ylcarbamoylmethanesulfinyl)octanoic acid hydroxyamide.83% @ 220 nm; LCMS (API-electrospray) m/z 391 (M+H)⁺ EXAMPLE 1923(1-Hydroxycarbamoyl-heptylsulfonyl)-benzoic acid hydroxarmide. 72% @215 nm EXAMPLE 1933-[4(1-Hydroxycarbamoyl-heptylsulfonyl)-phenyl-propionic acidhydroxyamide. 67% @ 215 nm EXAMPLE 1942-(1H-Imidazole-2-sulfonyl)-octanoic acid hydroxamide. 95% @ 215 nm;LCMS (API-electrospray) m/z 290 (M+H)⁺ EXAMPLE 1952-(Thiazol-2-ylsulfonyl)octanoic acid hydroxyamide. 91% @ 215 nm; LCMS(API-electrospray) m/z 307 (M+H)⁺ EXAMPLE 1962-(Quinoline-8-sulfonyl)-octanoic acid hydroxyamide. 94% @ 220 nm; LCMS(API-electrospray) m/z 351 (M+H)⁺ EXAMPLE 1972-(Naphthalen-2-ylcarbamoymethanesulfonyl)-octanoic acid hydroxyamide.79% @ 220 nm; LCMS (API-Electrospray) m/z 407 (M+H)⁺ EXAMPLE 1982-(2,5-Dioxo-imidazolidin-4-ylmethylsulfonyl)-octanoic acidhydroxyamide. 97% @ 215 nm EXAMPLE 199

Step A:Displacement of bromide with 4fluorothiophenol.

The 2-bromo hydroxymate resin prepared in Example 160, Step A (9.4 g,1.2 meq/g) was placed in a peptide synthesis vessel and suspended in THF(50 mL). 4Fluorothiophenol (6.6 g, 5.0 eq.), sodium iodide (7.7 g, 5.0eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 4.6 mL, 3.0 eq.) wereadded. The reaction was shaken at room temperature for 12-16 hours, thenfiltered and washed with DMF (2×30 mL), DMF:water 9:1 (2×30 mL), DMP (30mL), MeOH (2×20 mL), and DCM (2×20 mL). The resin was dried in vacuo atroom temperature.

Step B:Coupling of 2-(4fluorobenzenesulfanyl)-octanoic acid hydroxyamideresin with benzyl alcohol.

2-(4Fluorobenzenesulfanyl)-octanoic acid hydroxyamide resin prepared inStep A (330 mg, 1.1 meq/g) was suspended in DMF (2.0 mL) and benzylalcohol (731 mg, 15 eq.) and sodium hydride (237 mg, 15 eq.) were added.The reaction was heated to 80° C. for 15 hours while shaking on anorbital shaker. After cooling to room temperature the mixture wasfiltered and washed with DMF (2×2 mL), DMF:water 9:1 (2×3 mL), MeOH (2×2mL), and DCM (2×2 mL). The resin was dried in vacuo at room temperature.

Step C:Oxidation of sulfide to sulfoxide.

2-(4Benzyloxy-phenylsulfanyl)-octanoic acid hydroxyamide resin preparedin Step B (110 mg, 1.1 meq/g) was suspended in DCM (2.2 mL) and 70%tert-butylhydroperoxide (0.73 mL) benzenesulfonic acid (36 mg,) wereadded. The reaction mixture was shaken on an orbital shaker at roomtemperature for 12-24 hours. The reaction was filtered and washed withDCM (2×2 mL), DMF (2×2 ml), MeOH (2×2 mL), and DCM (2×2 mL). The resinwas dried in vacuo at room temperature.

Step D:Oxidation of sulfide to sulfone.

2-(4Benzyloxy-phenylsulfanyl)-octanoic acid hydroxyamide resin preparedin Step B (110 mg, 1.1 meq/g) was suspended in DCM (2.2 mL) and mCPBA(132 mg) was added. The reaction mixture was shaken on an orbital shakerat room temperature for 12-24 hours. The reaction was filtered andwashed with DCM (2×2 mL), DMF (2×2 mL), MeOH (2×2 mL), and DCM (2×2 mL).The resin was dried in vacuo at room temperature.

Step E:Cleavage of 2-(4benzyloxy-benzenesulfanyl)-octanoic acidhydroxyamide from resin.

The 2-(4-benzyloxy-phenylsulfanyl)octanoic acid hydroxyamide resinprepared in Step B (110 mg, 1.2 meq/g) was suspended in DCM (1.0 mL) andTFA (1.0 mL) was added. The reaction was shaken for 1 hour at roomtemperature. The reaction was filtered and the resin washed with DCM(2×1 mL). The filtrate and the washing were combined and concentrated todryness on a Savant SpeedVac Plus. Methanol (1 mL) was added and themixture concentrated. The crude product was dissolved in DMSO:methanol(1:1, 2 mL) and purified by reverse phase HPLC under the conditionsdescribed below:

Column:ODS-A, 20 mm×50 mm, 5 μm particle size (YMC, Inc. Wilmington,N.C.

Solvent Gradient Time Water Acetonitrile 0.0 95  5 25 min.  5 95 FlowRate: 15 mL/min.

2-(4-Benzyloxy-phenylsulfanyl)-octanoic acid hydroxyamide 100% @ 215 nm;LCMS (API-electrospray) m/z 374 (M+H)⁺.

The hydroxamic acid compounds of Examples 200-220 are synthesized usingappropriate starting materials and following the steps in example 199:

EXAMPLE 200 2-(4Butoxy-benzenesulfanyl)-octanoic acid hydroxyamide 100%@ 215 nm; LCMS (API-electrospray) m/z 374 (M+H)⁺ EXAMPLE 2012-[4(2-Piperazine-1-yl-ethoxy)-benzenesulfanyl]-octanoic acidhydroxyamide 98% @ 215 nm; LCMS (API-electrospray) m/z 340 (M+H)⁺EXAMPLE 202 2-[4-(5-Hydroxy-pentyloxy)-phenylsulfanyl]-octanoic acidhydroxyamide 65% @ 215 nm.; LCMS (API-electrospray) m/z 370 (+H)⁺EXAMPLE 203 2-[4(3-Pyridin-2-yl-propoxy)-benzenesulfanyl]-octanoic acidhydroxyamide 95% @ 215 nm; LCMS (API-electrospray) m/z 403 (M+H)⁺EXAMPLE 204 2-(4Benzyloxy-phenylsulfinyl)-octanoic acid hydroxyamide100% @ 215 nm EXAMPLE 205 2-(4Butoxy-benzenesulfinyl)-octanoic acidhydroxyamide 98% @ 215 nm EXAMPLE 2062-[4-(2-Piperazine-1-yl-ethoxy)-benzenesulfinyl]-octanoic acidhydroxyamide 98% @ 215 nm EXAMPLE 2072-[4-(3-Pyridin-2-yl-propoxy)-benzenesulfinyl]-octanoic acidhydroxyamide 99% @ 215 nm EXAMPLE 2082-(4Benzyloxy-phenylsulfonyl)-octanoic acid hydroxyamide 100% @ 215 nm

Example 209

2-(4-Butoxy-benzenesulfonyl)-octanoic acid hydroxyaride 100% @ 215 nmEXAMPLE 210 2-[4(2-Piperazine-1-yl-ethoxy)-benzenesulfonyl]-octanoicacid hydroxyamide 97% @ 215 nm EXAMPLE 2112-[4-(3-Pyridin-2-yl-propoxy)-benzenesulfonyl]octanoic acid hydroxyamide100% @ 215 nm EXAMPLE 2122-(4(1-Methyl-pyrrolidin-3-yloxy)-benzenesulfanyl]-octanoic acidhydroxyamide 91% @ 215 nm; LCMS (API-electrospray) m/z 367 (M+H)⁺EXAMPLE 213 2-[4-(1-Ethyl-propoxy)-benzenesulfanyl]-octanoic acidhydroxarmide 100% @ 215 nm; LCMS (API-electrospray) m/z 354 (M+H)⁺EXAMPLE 214 2-[4-(Tetrahydro-pyran-4-yloxy)-benzenesulfanyl]-octanoicacid hydroxyamide 97% @ 215 nm; LCMS (API-electrospray) m/z 368(M+H)^(+.) EXAMPLE 2152-[4-(1-Methyl-pyrrolidin-3-yloxy)-benzenesulfinyl]-octanoic acidhydroxyamide 96% @ 215 nm EXAMPLE 2162-[4-(1-Ethyl-propoxy)-benzenesulfinyl]-octanoic acid hydroxyamide 97% @215 nm EXAMPLE 2172-[4(Tetrahydro-pyran4-yloxy)-benzenesulfinyl]-octanoic acidhydroxyamide 97% @ 215 nm EXAMPLE 2182-[4(1-Methyl-pyrrolidin-3-yloxy)-benzenesulfonyl]-octanoic acidhydroxyamide 96% @ 215 nm EXAMPLE 2192-[4(1-Ethyl-propoxy)-benzenesulfonyl]-octanoic acid hydroxyamide 100% @215 nm EXAMPLE 2202-[4-(Tetrahydro-pyran-4-yloxy)-benzenesulfonyl]-octanoic acidhydroxyamide 100% @ 215 nm EXAMPLE 221

Step A:Displacement of bromide with 4-bromothiophenol.

The 2-bromo-octanoic acid hydroxymate resin prepared in

Example 160, Step A (5.0 g, 1.1 meq/g) was placed in a peptide synthesisvessel and suspended in THF (60 mL). 4-Bromothiophenol (5.2 g, 5.0 eq.),sodium iodide (4.1 g, 5.0 eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU, 2.5 mL, 3.0 eq.) were added. The reaction was shaken at roomtemperature for 12-16 hours, then filtered and washed with DMF (2×30mL), DMF:water 9:1 (2×30 mL), DMF (30 mL), MeOH (2×30 mL), and DCM (2×30mL). The resin was dried in vacuo at room temperature.

Step B:Oxidation of sulfide to sulfoxide.

2-(4-Bromobenzenesulfanyl)-octanoic acid hydroxyamide resin prepared inStep A (4.4 g, 1.1 meq/g) was suspended in DCM (60 mL) and 70%tert-butylhlydroperoxide (30 mL) benzenesulfonic acid (1.5 g) wereadded. The reaction mixture was shaken on an orbital shaker at roomtemperature for 12-24 hours. The reaction was filtered and washed withDCM (2×30 mL), DMF (2×30 mL), MeOH (2×30 mL), and DCM (2×30 mL). Theresin was dried in vacuo at room temperature.

Step C:Oxidation of sulfide to sulfone.

2-(4-Bromobenzenesulfanyl)-octanoic acid hydroxyamide resin prepared inStep B (4.4 g, 1.1 meq/g) was suspended in DCM (60 mL) and mCPBA (5.2 g)was added. The reaction mixture was shaken on an orbital shaker at roomtemperature for 12-24 hours. The reaction was filtered and washed withDCM (2×30 mL), DMF (2×30 mL), MeOH (2×30 mL), and DCM (2×30 mL). Theresin was dried in vacuo at room temperature.

Step D:Coupling of 2-(4bromobenzenesulfinyl)-octanoic acid hydroxyamideresin with 4-chlorobenzeneboronic acid.

2-(4-Bromobenzenesulfinyl)-octanoic acid hydroxyamide resin prepared inStep B (150 mg, 1.1 meq/g) was suspended in DME (2.0 mL) and nitrogengas bubbled through the suspension for 1-2 minutes.4-Chlorobenzeneboronic acid (51.6 mg, 2 eq.),tetrakis(triphenylphosphine) palladium(0) (19.07 mg, 0.1 eq.) and sodiumcarbonate (2 M solution, 0.825 mL, 10 eq.) were added. The reaction washeated to 80° C. for 8 hours while shaking on an orbital shaker.

After cooling to room temperature the mixture was filtered and washedwith DME (2×2 mL), DMF:water 9:1 (2×3 mL), MeOH (2×2 mL), and DCM (2×2mL). The resin was dried in vacuo at room temperature.

Step E:Cleavage of 2-(4′-chloro-biphenyl4-sulfinyl)-octanoic acidhydroxyamide from resin.

The 2-(4′-chloro-biphenyl-4-sulfinyl)-octanoic acid hydroxyamide resinprepared in Step D (150 mg, 1.1 meq/g) was suspended in DCM (1.0 mL) andTFA (1.0 mL) was added. The reaction was shaken for 1 hour at roomtemperature. The reaction was filtered and the resin washed with DCM(2×1 mL). The filtrate and the washing were combined and concentrated todryness on a Savant SpeedVac Plus. Methanol (1 mL) was added and themixture concentrated. The crude product was dissolved in DMSO:methanol(1:1, 2 mL) and purified by reverse phase HPLC under the conditionsdescribed below:

Column:ODS-A, 20 mm×50 mm, 5 μm particle size (YMC, Inc. Winmington,N.C.

Solvent Gradient Time Water Acetonitrile 0.0 95  5 25 min.  5 95 FlowRate: 15 mL/min.

2-(4′-Chloro-biphenyl4-sulfinyl)-octanoic acid hydroxyamide 96% @ 215nm; LCMS (API-electrospray) m/z 394 (M+H)⁺.

The hydroxamic acid compounds of Examples 222-224 are synthesized usingappropriate starting materials and following the steps in example 221:

EXAMPLE 222 2-[4-(5-Chloro-thiophen-2-yl)-benzenesulfinyl]-octanoic acidhydroxyamide 100% @ 215 nm; LCMS (API-electrospray) n]/z 400 (M+H)⁺EXAMPLE 223 2-(4′-Chloro-biphenyl-4-sulfonyl)-octanoic acid hydroxyamide94% @ 215 nm; LCMS (API-electrospray) m/z 410 (M+H)⁺ EXAMPLE 2242-[4-(5-Chloro-thiophen-2-yl)-benzenesulfonyl]-octanoic acidhydroxyamide 85% @ 215 nm; LCMS (API-electrospray) m/z 416 (M+H)⁺EXAMPLE 225

Step A:Coupling of 2-(4bromobenzenesulfanyl)-octanoic acid hydroxyamideresin with N-(3-aminopropyl)-morpholine.

2-(4Bromobenzenesulfanyl)-octanoic acid hydroxyamide resin prepared inExample 199, Step A (100 mg, 1.1 meq/g) was suspended in dioxane (2.0mL) and nitrogen gas bubbled through the suspension for 1-2 minutes.N-(3-Aminopropyl)-morpholine (346 mg, 20 eq.),tris(dibenzylideneacetone)-dipalladium(0) (22 mg, 0.2 eq.),(S)-(-)-2,2′-bis(diphenylphosphino)-1,1 ′-binaphthyl((S)-BINAP, 60 mg,0.8 eq.) and sodium tert-butoxide (207 mg, 18 eq.) were added. Thereaction was heated to 80° C. for 8 hours while shaking on an orbitalshaker. After cooling to room temperature the mixture was filtered andwashed with DMF (2×2 mL), DMF:water 9:1 (2×3 mL), MeOH (2×2 mL), and DCM(2×2 mL). The resin was dried in vacuo at room temperature.

Step B:Cleavage of2-[4-(3-morpholin-4-yl-propylamino)-phenylsulfanyl]-octanoic acidhydroxyamide from resin.

The 2-[4-(3-morpholin-4-yl-propylamino)-phenylsulfanyl]-octanoic acidhydroxarmide resin prepared in Step A (100 mg, 1.1 meq/g) was suspendedin DCM (1.0 mL) and TFA (1.0 mL) was added. The reaction was shaken for1 hour at room temperature. The reaction was filtered and the resinwashed with DCM (2×1 mL). The filtrate and the washing were combined andconcentrated to dryness on a Savant SpeedVac Plus. Methanol (1 mL) wasadded and the mixture concentrated. The crude product was dissolved inDMSO:methanol (1:1, 2 mL) and purified by reverse phase HPLC under theconditions described below:

Column:ODS-A, 20 mm×50 mm, 5 μn particle size (YMC, Inc. Wilmington,N.C.

Solvent Gradient Time Water Acetonitrile 0.0 95  5 25 min.  5 95 FlowRate: 15 mL/min.

2-[4-(3-morpholin-4-yl-propylamino)-phenylsulfanyl]-octanoic acidhydroxyamide 88% @ 215 nm; LCMS (API-electrospray) m/z 410 (M+H)⁺.

The hydroxamic acid compounds of Examples 226-231 are synthesized usingappropriate starting materials and following the steps in this example:

EXAMPLE 226 2-[4(Bipheny-4-ylamino)-phenylsulfanyl]-octanoic acidhydroxyamide 95% @ 215 nm; LCMS (API-electrospray) m/z 435 (M+H)⁺EXAMPLE 227 2-[(Pyridin-4-ylamino)-phenylsulfanyl]-octanoic acidhydroxyamide 97% @ 215 nm; LCMS (API-electrospray) m/z 360 (M+H)⁺EXAMPLE 228 2-(4Cyclopentylamino-phenylsulfanyl)-octanoic acidhydroxyamide 77% @ 215 nm; LCMS (API-electrospray) m/z 351 (M+H)⁺EXAMPLE 229 2-(4Methylamino-phenylsulfanyl)-octanoic acid hydroxyamide99% @ 215 nm; LCMS (API-electrospray) m/z 297 (M+H)⁺ EXAMPLE 2302-(4Piperidin-1-yl-phenylsulfanyl)-octanoic acid hydroxarmide 72% @ 215nm; LCMIS (API-electrospray) m/z 351 (M+H)⁺ EXAMPLE 2312-(4-Piperidin-1-yl-phenylsulfanyl)-octanoic acid hydroxyamide 74% @ 215nm; LCMS (API-electrospray) m/z 352 (M+H)⁺ EXAMPLE 232

Step A:Displacement of bromide with 4hydroxythiophenol.

The 2-bromo-octanoic acid hydroxymate resin prepared in Example 160,Step A (15.0 g, 1.1 meq/g) was placed in a peptide synthesis vessel andsuspended in THF (120 mL). 4-Hydroxythiophenol (11.3 g, 5.0 eq.), sodiumiodide (13.5 g, 5.0 eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU,8.1 mL, 3.0 eq.) were added. The reaction was shaken at room temperaturefor 12-16 hours, then filtered and washed with DMF (2×60 mL), DMF:water9:1 (2×60 mL), DMF (60 mL), MeOH (2×60 mL), and DCM (2×60 mL). The resinwas dried in vacuo at room temperature.

Step B:Coupling of 2-(4hydroxybenzenesulfanyl)-octanoic acidhydroxyamide resin with benzene sulfonyl chloride.

2-(4-Hydroxybenzenesulfanyl)-octanoic acid hydroxyamide resin preparedin Step A (240 mg, 1.2 meq/g) was suspended in DCM (3.0 mL). Benzenesulfonyl chloride (225 mg, 5 eq.), and triethylamine (0.06 mL, 2 eq.)were added. The reaction was shaken on an orbital shaker at roomtemperature for 8 hours, then filtered and washed with DME (2×2 mL),DMF:water 9:1 (2×3 mL), MeOH (2×2 mL), and DCM (2×2 mL). The resin wasdried in vacuo at room temperature.

Step C:Oxidation of sulfide to sulfoxide.

Benzenesulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfanyl)-phenyl esterresin prepared in Step B (80 mg, 1.2 meq/g) was suspended in DCM (3 mL)and 70% tert-butylhydroperoxide (1 mL) benzenesulfonic acid (23 mg) wereadded. The reaction mixture was shaken on an orbital shaker at roomtemperature for 12-24 hours. The reaction was filtered and washed withDCM (2×3 mL), DMF (2×3 mL), MeOH (2×3 mL), and DCM (2×3 mL). The resinwas dried in vacuo at room temperature.

Step D:Oxidation of sulfide to sulfone.

Benzenesulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfanyl)-phenyl esterresin prepared in Step B (80 mg, 1.2 meq/g) was suspended in DCM (3 mL)and mCPBA (84 mg) was added. The reaction mixture was shaken on anorbital shaker at room temperature for 12-24 hours. The reaction wasfiltered and washed with DCM (2×3 mL), DMF (2×3 mL), MeOH (2×3 mL), andDCM (2×3 mL). The resin was dried in vacuo at room temperature. StepE:Cleavage of benzenesulfonic acid4-(1-hydroxycarbamoyl-heptylsulfanyl)-phenyl ester resin.

The benzenesulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfanyl)-phenylester resin prepared in Step B (80 mg, 1.2 meq/g) was suspended in DCM(1.0 mL) and TFA (1.0 mL) was added. The reaction was shaken for 1 hourat room temperature. The reaction was filtered and the resin washed withDCMI (2×1 mL). The filtrate and the washing were combined andconcentrated to dryness on a Savant SpeedVac Plus. Methanol (1 mL) wasadded and the mixture concentrated The crude product was dissolved inDMSO:methanol (1:1, 2 mL) and purified by reverse phase HPLC under theconditions described below:

Column:ODS-A, 20 mm×50 mm, 5 μm particle size (YMC, Inc. Wilmington,N.C.

Solvent Gradient Time Water Acetonitrile 0.0 95  5 25 min.  5 95 FlowRate: 15 mL/min.

Benzenesulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfanyl)-phenyl ester91% @ 215 nm; LCMS (API-electrospray) m/z 424 (M+H)⁺.

The hydroxamic acid compounds of Examples 233-240 are synthesized usingappropriate starting materials and following the steps in example 232:

EXAMPLE 233 2,5-Dichloro-thiophene-3-sulfonic acid4-(1-hydroxycarbamoyl-heptylsulfanyl)-hydroxyaride 98% @ 215 nm; LCMS(API-electrospray) m/z 498 (M+H)⁺ EXAMPLE 234 Ethanesulfonic acid4-(1-hydroxycarbamoyl-heptylsulfanyl)-hydroxyamide. 72% @ 215 nm; LCMS(API-electrospray) m/z 376 (M+H)⁺ EXAMPLE 2355-Chloro-1,3-dimethyl-1H-pyrazole4-sulfonic acid4-(1-hydroxycarbamoyl-heptylsulfinyl)-hydroxyamide 99% @ 215 nm; LCMS(API-electrospray) m/z 492 (M+H)⁺ EXAMPLE 2362,5-Dichloro-thiophene-3-sulfonic acid4-(1-hydroxycarbamoyl-heptylsulfinyl)-hydroxyamide 96% @ 215 nm; LCMS(API-electrospray) m/z 514 (M+H)⁺ EXAMPLE 2375-Pyridin-2-yl-thiophene-2-sulfonic acid4-(1-hydroxycarbamoyl-heptylsulfinyl)-hydroxy amide 96% @ 215 nm; LCMS(API-electrospray) m/z 523 (M+H)⁺ EXAMPLE 238 2-Nitro-benzenesulfonicacid 4-(1-hydroxycarbamoyl-heptylsulfonyl)-hydroxyamide 97% @ 215 nm;LCMS (API-electrospray) m/z 501 (M+H)⁺ EXAMPLE 2393-Bromo-2-chloro-thiophene-2-sulfonic acid4-(1-hydroxycarbamoyl-heptylsulfonyl)-hydroxyaride 97% @ 215 nm; LCMS(API-electrospray) m/z 576 (M+H)⁺ EXAMPLE 240 Benzo[1,2,5]thiadiazole-4-sulfonic acid4-(1-hydroxycarbamoyl-heptylsulfonyl)-hydroxyamide 83% @ 215 nm; LCMS(API-electrospray) m/z 514 (M+H)⁺ EXAMPLE 2411-Benzyl-4-(4-benzyloxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxarmide

To a stirred solution of 4-methoxybenzenethiol (2.8 gm 20 mmol) andanhydrous K₂CO₃ (10 gm, excess) in dry acetone (100 ml), a-bromo ethylacetate (3.3 gm, 20 mmol) was added in a round bottom flask and thereaction mixture was heated at reflux for 8 hours with good stirring. Atthe end, the reaction mixture was allowed to cool and the potassiumsalts were filtered off and the reaction mixture was concentrated. Theresidue was extracted with chloroform and washed with H₂O and 0.5 N NaOHsolution. The organic layer was further washed well with water, driedover MgSO₄, filtered and concentrated. (4-methoxy-phenylsulfanyl)-aceticacid ethyl ester was isolated as pale yellow oil. Yield:4.4 g (100%);MS; 227 (M+H)⁺

To stirred solution of (4-methoxy-phenylsulfanyl)-acetic acid ethylester (4.4 g, 20 mmol), anhydrous K₂CO₃ (10 gm, excess) in dry acetone(100 ml) benzyl bromide (3.5 g, 20 mmol) was added and refluxed for 4hrs. At the end, reaction mixture was filtered , concentrated and theresidue was extracted with chloroform. It was washed well with water,dried and concentrated. The crude product obtained was converted to(4-benzyloxy-phenylsulfonyl)-acetic acid ethyl ester by oxidaizing withchloro perbenzoic acid as described in the example 83. Low meltingsolid. Yield:6.6 g, 97%; MS:335 (M+1)

To a stirred solution of bis-(2-chloro-ethyl)-benzyl amine hydrochloride(6.6 g, 24.7 mmol), 18-Crown-6 (500 mg), and anhydrous K₂CO₃ (30 gm,excess) in dry acetone (250 ml), (4-benzyloxy-phenylsulfonyl)-aceticacid ethyl ester (8.01 gm, 24 mmol) was added in a round is bottom flaskand the reaction mixture was heated at reflux for 16 hours with goodstirring. At the end, the reaction mixture was allowed to cool and thepotassium salts were filtered off and the reaction mixture wasconcentrated. The residue was extracted with chloroform and washed withH₂O. The organic layer was further washed well with water, dried overMgSO_(4,) filtered and concentrated. The dark brown reaction mixture waspurified by silica gel column chromatography by eluting it with 30%ethylacetate:hexane and the product4-(4-Benzyloxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acidethyl ester was isolated as Brown oil. Yield:6.5 g, 55%; MS:494 (M+H)

4-(4-Benzyloxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acidethyl ester (5.0 g, 10.1 mmol) was dissolved in MeOH/THF (1:1, 200 ml)and stirred at room temperature for 72 hrs. At the end reaction mixturewas concentrated and the product was neutralized with con. HCl bydissolving it in water (200 ml). After the neutralization reactionmixture was concentrated to dryness. Ice cold water (100 ml) was addedto the solid and filtered. The product4-(4-Benzyloxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acidwas dried at 50 C and taken to next step with out any purification.Colorless solid. MP:66-68; Yield:4.3 g, 91% ; MS:466 (M+H) Starting from4-(4-Benzyloxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acid(4.65 g, 10.0 mmol) and following the procedure outlined in example 83,1.1 g of 4-(4-Benzyloxy-benzenesulfonyl)-1-benzyl-piperidine~carboxylicacid hydroxyamide was isolated as a colorless solid. Yield 21%; mp 89°C.; MS:481.1 1H No (300 MHz, DMSO-d6):δ2.27 (m, 3H), 2.76-2.79 (m, 2H),3.43 (m, 4H),4.30 (s, 2H), 7.14-7.17 (d,2H), 7.50-7.73 (m, 5H), 9.37(s,1H), 10.53 (s,1H), 11.18 (s,1H).

EXAMPLE 2424-(4-Butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid hydroxyamide

From 2-[(2-Hydroxy-ethyl)-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-amine wasprepared according to the general method outlined in example 83 startingfrom diethanolamine (15.0 g, 150). and4-(2-piperidin-1-yl-ethoxy)-benzyl chloride (5.9 g, 20 mmol). Yield 5.5g, (85%);

Brown semi-solid; MS:323 (M+H)⁺

Bis-(2-chloro-ethyl)-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-amine wasprepared according to the general method outlined in example 83 startingfrom 2-[(2-Hydroxy-ethyl)-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-amine(3.22 g, 10 mmol). Yield 4.0 g (92%); brown semi-solid; MS: 361.1 (M+H)⁺

4-(4-Butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method outlinedin example 83 starting from from 4-(butoxy-benzenesulfonyl) acetic acidethyl ester (6.0 g, 20 mmol) andBis-(2-chloro-ethyl)-[4(2-piperidin-1-yl-ethoxy)-benzyl]-amine (8.6 g,20 mmol). Yield 8.0 g (68%); brown oil; MS:587.7 (M+H)⁺

4-(4-Butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylicacid was prepared starting from4-(4-Butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylicacid ethyl ester (5.8 g, 10 mmol) dissolved in THF:methanol 3:1 and 10 NNaOH (40 ml). The resulting reaction mixture was worked up as outlinedin example 83. Yield 4.8 g (86%); Spongy brown solid; mp 98° C.;MS:559.6 (M+H)⁺

Starting from4-(4-butoxy-benzenesulfonyl)-1-[4(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylicacid (5.5 g, 10 mmol) and following the procedure outlined in example83, 2.4 g of4-(4-butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylicacid hydroxy amide was isolated as a pale yellow solid. Yield 41%; mp155° C. (HCl); MS:574 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆):δ0.9 (t, 3H),1.1-1.8 (m, 6H), 1.9 (m, 4H), 2.3 (m, 4H), 2.8 (m, 6H), 3.2-3.6 (m, 8H),4.2 (m, 2H), 6.9-7.8 (m, 8H), 9.1 (s, 1H), 10.8 (bs, 1H).

EXAMPLE 2434(4-Butoxy-benzenesulfonyl)-1-[3-(2-morpholinyl-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylicacid hydroxyamide

Bis-(2-hydroxy-ethyl)-[3-(2-morpholin-1-yl-ethoxy)-benzyl]-amine wasprepared according to the general method outlined in example 83 startingfrom diethanolamine (15.0 g, 150). and3-(2-morpholin-1-yl-ethoxy)-benzyl chloride (5.9 g, 20 mmol). Yield 6.2g, (95%); Brown semi-solid; MS:325 (M+H)⁺

Bis-(2-chloro-ethyl)-[3-(2-morpholin-1-yl-ethoxy)-benzyl]-amine wasprepared according to the general method outlined in example 83 startingfrom Bis-(2-Hydroxy-ethyl)-[3-(2-morpholin-1-yl-ethoxy)-benzyl]-amine(3.24 , 10 mmol). Yield 4.0 g (92%); brown semi-solid; MS:363.1 (M+H)⁺

4-(4-Butoxy-benzenesulfonyl)-1-[3-(2-morpholin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid ethyl ester was prepared according to the generalmethod outlined in example 83 starting from from4-(butoxy-benzenesulfonyl) acetic acid ethyl ester (6.0 g, 20 mmol) andBis-(2-chloro-ethyl)-[3-(2-morpholin-1-yl-ethoxy)-benzyl]-amine (8.6 g,20 mmol). Yield 8.5 g (72%); brown oil; MS:589.7 (M+H)⁺

4-(4-Butoxy-benzenesulfonyl)-I-[3-(2-morpholin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid wasprepared starting from4-(4-Butoxy-benzenesulfonyl)-1-[3-(2-morpholin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylicacid ethyl ester (5.8 g, 10 mmol) dissolved in THF:methanol 3:1 and 10 NNaOH (40 ml). The resulting reaction mixture was worked up as outlinedin example 83. Yield 4.8 g (85%); Spongy brown solid; MS:561.6 (M+H)⁺

Starting from4-(4-butoxy-benzenesulfonyl)-1-[3-(2-morpholin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylicacid (5.6 g, 10 mmol) and following the procedure outlined in example83, 4.02 g of4-(4-butoxy-benzenesulfonyl)-1-[3-(2-morpholin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylicacid hydroxy amide was isolated as a pale yellow solid. Yield 62%; mp123° C. (HCl); MS:576 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆):δ0.9 (t, 3H),1.4 (m, 2H), 1.8 (t, 2H), 2.3-4.7 (m, 24H), 7.0-7.8 (m, 8H), 9.1 (s,1H), 10.8 (bs, 1H).

EXAMPLE 244 1-Methyl-4-(4butoxy-benzenesulfonyl)-piperidine-4-carboxylicacid hydroxyamide

1-Methyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethylester was prepared according to the general method outlined in example83 starting from 4-(butoxy-benzenesulfonyl) acetic acid ethyl ester (3g, 10 mmol) and methyl-bis-(2-chloro-ethyl)-amine (2.2 g, 11.6 mmol).Yield 4.0 g, (98%); low melting brown solid; MS:384 (M+H)⁺

1-Methyl-4-(butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid wasprepared starting from1-methyl-4-(4butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethylester (7.6 g, 20 mmol) dissolved in methanol (300 ml) and 10 N NaOH (35ml). The resulting reaction mixture was worked up outlined in example83. Yield 6.0 (84%); white solid; mp 195° C.; MS:356.4 (M+H)⁺

Starting from1-methyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid (4.0g, 11.2 mmol) and following the procedure outlined in example 83, 3.9 gof 1-methyl4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide was isolated as a yellow powder. Yield 85%; mp 118° C.;MS:371 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d6):δ0.9 (t, 3H), 1.45 (q, 2H), 1.8(q, 2H), 2.1 (s, 3H), 2.3 (d, J=11.4 Hz, 2H), 2.5-3.7 (m, 8H), 4.1 (t,2H), 7.16 (d, 2H), 7.67 (d, 2H)

EXAMPLE 245 1-Ethyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylicacid hydroxyamide

1-Ethyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethylester was prepared according to the general method outlined in example83 starting from 4-(butoxy-benzenesulfonyl) acetic acid ethyl ester (3g, 10 mmol) and ethyl-bis-(2chloro-ethyl)-amine (2.2 g, 10.6 mmol).Yield 3.5 g, (88%); low melting brown solid; MS: 398 (M+H)⁺

1-Ethyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid wasprepared starting from1-ethyl4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethylester (7.94 g, 20 mmol) dissolved in methanol (300 ml) and 10 N NaOH (35ml). The resulting reaction mixture was worked up as outlined in example83. Yield 6.5 g (88%); white solid; mp 162° C.; MS:370 (M+H)⁺

Starting from1-ethyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid (3.7g, 10 mmol) and following the procedure outlined in example 83, 3.2 g of1-ethyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide was isolated as a yellow powder. Yield 76%; mp 98° C.;MS:385 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆):δ0.9 (t, 3H), 1.2 (t, 3H), 1.46(q, 2H), 1.9 (q, 2H), 2.3 (d, J=11.4 Hz, 2H), 2.5-3.6 (m, 10H), 7.16 (d,2H), 7.67 (d, 2H)

EXAMPLE 2461-n-Butyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide

1-n-Butyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acidethyl ester was prepared according to the general method outlined inexample 83 starting from 4-(butoxy-benzenesulfonyl) acetic acid ethylester (3 g, 10 mmol) and n-butyl-bis-(2-chloro-ethyl)-amine (2.0 g, 10.1mmol). Yield 3.8, (89%); low melting brown solid; MS:426 (M+H)⁺

1-n-Butyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid wasprepared starting from1-n-Butyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acidethyl ester (8.5 g, 20 mmol) dissolved in methanol (300 ml) and 10 NNaOH (35 ml). The resulting reaction mixture was worked up as outlinedin example 83. Yield 7.5 g (88%); white solid; mp 182° C.; MS:398 (M+H)⁺

Starting from1-n-butyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid (3.9g, 10 mmol) and following the procedure outlined in example 83, 1.8 g of1-n-butyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acidhydroxyamide was isolated as a yellow powder. Yield 40%; mp 121° C.;MS:413 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆):δ0.9-1.0 (m, 6H), 1.2-1.8 (m,8H), 2.2-2.8 (m, 8H), 3.0-3.6 (m, 4H), 4.2 (t, 2H), 7.16 (d, 2H), 7.67(d, 2H), 9.3 (bs, 1H), 10.3 (bs, 1H), 11.1 (bs,1H).

EXAMPLE 247 [(4-Chloro-phenoxy)-phenylsulfanyl]-acetic acid ethyl ester

A mixture of 4-bromo chlorobenzene (1.92 g, 10 mmol),(4-Hydroxy-phenylsulfanyl)-acetic acid ethyl ester (2.12 g, 10 mmol),sodium hydride (460 mg, 10 mmol) and copper(II) chloride (500 mg) wasrefluxed in anhydrous pyridine (50 ml) for 12 hrs. The reaction mixturewas carefully quenched with ice cold water and acidified withconcentrated HCl. The product was extracted with choroform, washed wellwith water; dried and concentrated. The product was purified by silicagel column chromatography by eluting with 30% ethyl acetate :hexane.Yield 2.5 g (77%); Colorless low melting solid; MS:323 (M+H)⁺.Alternatively the title compound may be prepared from4-(4-chloro-phenoxy)-benzenethiol and bromo ethyl acetate as describedin example 83.

EXAMPLE 248 [4-(4Chloro-phenoxy)-benzenesulfonyl]-acetic acid ethylester

[4-(4-Chloro-phenoxy)-benzenesulfonyl]-acetic acid ethyl ester wasprepared according to the general method outlined in example 83 startingfrom [4-(4-chloro-phenoxy)-phenylsulfanyl]-acetic acid ethyl ester (3.23g, 10 mmol) and oxone (10 g). Yield 3.5g (99%); oil; MS:356EI (M+H)⁺

EXAMPLE 249 4-[4-(4-chloro-phenoxy)-benzenesulfonyl]1-methyl-piperidine-4-carboxylic acid hydroxyamide

4-[4-(4Chloro-phenoxy)-benzenesulfonyl]-1-methyl-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method outlinedin example 83 starting from[4-(4-chloro-phenoxy)-benzenesulfonyl]-acetic acid ethyl ester (2.0 g,5.6mmol) and mechlorethanmine hydrochloride (Aldrich), (1.9 g, 10 mmol).Yield 2g (81%); brown oil; MS:438 (M+H)⁺

4-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-1-methyl-piperidine-4-carboxylicacid was prepared starting from4[4-(4-chloro-phenoxy)-benzenesulfonyl]-1-methyl-piperidine-4-carboxylicacid ethyl ester (4.3 g, 10 mmol) dissolved in THF:methanol (3:1 150 ml)and 10 N NaOH (100 ml). The resulting reaction mixture was worked up asoutlined in example 83. Yield 3.5g (86%); white solid; mp 185° C.;MS:410(M+H)⁺

Starting from4-[4(4-chloro-phenoxy)-benzenesulfonyl]-1-methyl-piperidine-4-carboxylicacid (1.0 g, 2.4 mmol) and following the procedure outlined in example83, 460 mg of4-[4-(4-chloro-phenoxy)-benzenesulfonyl]1-methyl-piperidine-4-carboxylicacid hydroxyamide was isolated as a HCl salt, a white powder. Yield 41%;mp 52° C.; MS: 426 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆):δ1.3 (s, 3H),2.2-2.9 (m, 6H), 3.5 (bd, 2H), 7.2-7.9 (m, 8H), 8.1 (s, 1H), 11.0 (bs,1H).

EXAMPLE 2504-[4-(4-chloro-phenoxy)-benzenesulfonyl]1-ethyl-piperidine-4-carboxylicacid hydroxyamide

4-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-1-ethyl-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method outlinedin example 83 starting from[4-(4-chloro-phenoxy)-benzenesulfonyl]-acetic acid ethyl ester (4 g,11.3 mmol) and ethyl-bis-(2-chloro-ethyl)-amine (2.32 g, 16.9 mmol).Yield 3.36 g (66%); brown oil; MS: 452.0 (M+H)⁺

4-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-1-ethyl-piperidine-4-carboxylicacid was prepared starting from4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-1-ethyl-piperidine-4-carboxylicacid ethyl ester (3.02 g, 6.7 mmol) dissolved in THF:methanol (3:1 150ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked upas outlined in example 83. Yield 1.8 g (65%); white solid; mp 184° C.;MS:423.9 (M+H)⁺

Starting from4-[4-(4-choro-phenoxy)-benzenesulfonyl]-1-ethyl-piperidine-4-carboxylicacid (1.75 g, 4.14 mmol) and following the procedure outlined in example83, 650 mg of4-[4-(4-chloro-phenoxy)-benzenesulfonyl]1-ethyl-piperidine-4-carboxylicacid hydroxyamide was isolated as a HCl salt, a white powder. Yield 33%;mp 158° C.; MS: 438.9 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆):δ1.78 (t, J=7.23Hz, 3H), 2.23-2.27 (m, 2H), 2.51-2.73 (m, 4H), 3.04 (m, 2H), 3.81 (d,J=24 Hz, 2H), 7.16-7.27 (m, 4H), 7.50-7.57 (m, 2H), 7.76 (d, J=7 Hz,2H), 9.34 (s, 1H), 9.85 (s, 1H).

EXAMPLE 2511-Butyl-4-[4-(4chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid hydroxyamide

1-Butyl-4-[4-(4-choro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method outlinedin example 83 starting from [4(4-chloro-phenoxy)-benzenesulfonyl]-aceticacid ethyl ester (6 g, 18.3 mmol) and butyl-bis-(2-chloro-ethyl)-amine(5.2 g, 22 mmol). Yield 3.3 g (38%); yellow oil; MS: 480 (M+H)⁺

1-Butyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid was prepared starting from1-butyl-4-[4-(4-choro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid ethyl ester (3.3 g, 6.9 mmol) dissolved in THF:methanol (3:1 150ml) and 10 N NaOH (25 ml). The resulting reaction mixture was worked upas outlined in example 83. Yield 2.08 g (67%); white solid; mp 201° C.;MS: 451.9 (M+H)⁺

Starting from1-butyl-4-[4-(4-choro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid (2 g, 4.43 mmol) and following the procedure outlined in example83, 630 mg of1-butyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid hydroxyamide was isolated as a HCl salt, a white solid. Yield 31%;mp 212° C.; MS: 466.9 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆):670.87 (t, J=7.3Hz, 3H), 1.32 (m, 2H), 1.60 (m, 2H), 2.21 (m, 2H), 2.50 (m, 2H), 2.70(q, 2H), 3.00 (m, 2H), 3.57 (d, 2H), 7.16-7.26 (m, 4H), 7.49-7.56 (m,2H), 7.77 (d, J=9 Hz, 2H), 9.34 (s, 1H), 10.13 (s, 1H).

EXAMPLE 2521-Benzyl-4-[4-(4-choro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid hydroxyamide

1-Benzyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method outlinedin example 83 starting from[4-(4-chloro-phenoxy)-benzenesulfonyl]-acetic acid ethyl ester (6 g,16.9 mmol) and bis-(2chloro-ethyl)-benzyl amine (6.44 g, 24 mmol). Yield2.21 g (25%); yellow oil; MS: 513.9 (M+H)⁺

1-Benzyl-4-[4-(4-choro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid was prepared starting from1-benzyl-4-[4-(chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid ethyl ester (2.11 g, 4.1 mmol) dissolved in THF:methanol (3:1 150ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked upas outlined in example 83. Yield 1.11 g (56%); white solid; mp 201° C.;MS: 485.9 (M+H)⁺

Starting from1-benzyl-4-[4(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid (1 g, 2.06 mmol) and following the procedure outlined in example83, 430 mg of1-benzyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine4-carboxylicacid hydroxyamide was isolated as a HCl salt, an off white solid. Yield39%; mp 90.4° C.; MS: 500.9 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆):δ2.18-2.30(m, 2H), 2.73-2.81 (m, 4H), 3.36 (d, 2H), 4.28 (d, J=4.5 Hz, 2H),7.15-7.25 (m, 4H), 7.43-7.48 (m, 3H), 7.51-7.56 (m, 4H), 7.74 (d, J=9Hz, 2H), 9.53 (s, 1H), 10.47 (s, 1H).

EXAMPLE 253 [4-(3-methyl-butoxy)-phenylsulfanyl]-acetic acid ethyl ester

To stirred solution of (4-Hydroxy-phenylsulfanyl)-acetic acid ethylester (2.12 g, 10 mmol), k₂CO₃ (anhydrous, 10 g) and 1-bromo-3-methylbutane (3 g, excess) was added in boiling acetone. The reaction mixturewas refluxed for 24 hrs and cooled to room temperature. The reactionmixture was filtered and concentrated. The residue obtained wasextracted with chloroform; washed well with water and concentrated. Thecrude product obtained was taken to next step with out purification.Yield 2.7 g (94%); (M+H)⁺ 283.

EXAMPLE 254 [4-(3-methyl-butoxy)-phenylsulfonyl]-acetic acid ethyl ester

[4-(3-methyl-butoxy)-phenylsulfonyl]-acetic acid ethyl ester wasprepared according to the general method outlined in example 83 startingfrom [4-(3-methyl-butoxy)-phenylsulfanyl]-acetic acid ethyl ester (2.8g, 10 mmol) and oxone (10 g). Yield 3.0 g (99%); oil; MS: 314EI (M+H)⁺

EXAMPLE 2551-Benzyl-4-[4-3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid hydroxamide

1-Benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method outlinedin example 83 starting from [4-(3-methyl-butoxy)-phenylsulfonyl]-aceticacid ethyl ester (6.2 g, 20 mmol) and bis-(2-chloro-ethyl)-benzyl amine(6.44 g, 24 mmol). Yield 8 g (84%); yellow oil; MS: 474 (M+H)⁺

1-Benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid was prepared starting from1-Benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylicethyl ester (4.7 g, 10 mmol) dissolved in THF:methanol (3:1 150 ml) and10 N NaOH (20 ml). The resulting reaction mixture was worked up asoutlined in example 83. Yield 3 g (67%); white solid; mp 182° C.; MS:446 (M+H)⁺

Starting from1-Benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid (2.2 g, 5 mmol) and following the procedure outlined in example 83,1.82 g of1-Benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid hydroxyamide was isolated as a HCl salt, an off white solid. Yield73%; mp 106° C.; MS: 498 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆):δ0.8 (d, 6H),1.5 (m, 1H), 1.6-2.0 (m, 6H), 2.73-2.81 (m, 4H), 3.5 (d, 2H), 4.28 (d,J=4.5 Hz, 2H), 7.15-7.25 (m, 4H), 7.43-7.48 (m, 3H), 7.51-7.56 (m, 4H),7.74 (d, J=9 Hz, 2H), 9.53 (s, 1H), 10.47 (s, 1H).

EXAMPLE 2561-Butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid hydroxyamide

1-Butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method outlinedin example 83 starting from [4-(3-methyl-butoxy)-phenylsulfonyl]-aceticacid ethyl ester (6.2 g, 20 mmol) and butyl-bis-(2-choro-ethyl)-amine(5.2 g, 22 mmol). Yield 7 g (79%); yellow oil; MS: 440 (M+H)⁺

1-Butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid was prepared starting from1-Butyl-4-[4-(3-methyl-butoxy)-berzenesulfonyl]-piperidine-4-carboxylicethyl ester (4.4 g, 10 mmol) dissolved in THF:methanol (3:1 150 ml) and10 N NaOH (20 ml). The resulting reaction mixture was worked up asoutlined in example 83. Yield 3.2 g (77%); white solid; mp 188° C.; MS:412 (M+H)⁺

Starting from1-Butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid (2.0 g, 5 mmol) and following the procedure outlined in example 83,1.6 g of1-Butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid hydroxyamide was isolated as a HCl salt, an off white solid. Yield69%; mp 201° C.; MS: 464 (M+H)⁺.

EXAMPLE 257 [4-(2-Ethyl-butoxy)-phenylsulfanyl]-acetic acid ethyl ester

To stirred solution of (4Hydroxy-phenylsulfanyl)-acetic acid ethyl ester(2.12 g, 10 mmol), K₂CO₃ (anhydrous, 10 g) and 1-bromo-2-ethyl butane (3g, excess) was added in boiling acetone. The reaction mixture wasrefluxed for 24 hrs and cooled to room temperature. The reaction mixturewas filtered and concentrated. The residue obtained was extracted withchloroform; washed well with water and concentrated. The crude productobtained was taken to next step without purification. Yield 2.8 g (94%);(M+H)⁺ 297.

EXAMPLE 258 [4-(2-Ethyl-butoxy)-phenylsulfonyl]-acetic acid ethyl ester

[4-(2-Ethyl-butoxy)-phenylsulfonyl]-acetic acid ethyl ester was preparedaccording to the general method outlined in example 83 starting from[4-(2-ethyl-butoxy)-phenylsulfanyl]-acetic acid ethyl ester (2.96 g, 10mmol) and oxone (10 g). Yield 3.1 g (99%); oil; MS: 329EI (M+H)⁺

EXAMPLE 2591-Benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid hydroxyamide

1-Benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method outlinedin example 83 starting from [4-(2-ethyl-butoxy)-phenylsulfonyl]-aceticacid ethyl ester (6.4 g, 20 mmol) and bis-(2-chloro-ethyl)-benzyl amine(6.44 g, 24 mmol). Yield 8 g (82%); yellow oil; MS: 488 (M+H)⁺

1-Benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid was prepared starting from1-Benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylicethyl ester (4.8 g, 10 mmol) dissolved in THF:methanol (3:1 150 ml) and10 N NaOH (20 ml). The resulting reaction mixture was worked up asoutlined in example 83. Yield 4 g (87%); Semi solid; MS: 460 (M+H)⁺

Starting from1-Benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid (2.2 g, 5 mmol) and following the procedure outlined in example 83,1.02 g of1-Benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylicacid hydroxyamide was isolated as a HCl salt, an off white solid. Yield40%; mp 114° C.; MS: 512 (M+H)⁺.

EXAMPLE 2604-(4-butoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylicacid hydroxyamide

4-(4-Butoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method outlinedin example 83 starting from 4-(4-butoxy-benzenesulfonyl)-acetic acidethyl ester (20 g, 77.5 mmol) andbis-(2-chloro-ethyl)-(3-methoxy-benzyl)-amine (34 g, 116 mmol). Yield9.53 g (25%); brown oil; MS: 490.2 (M+H)⁺

4-(4-Butoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylicacid was prepared starting from4-(4-methoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylicacid ethyl ester (2.61 g, 5.34 mmol) dissolved in THF:methanol (3:1 150ml) and 10 N NaOH (15 ml). The resulting reaction mixture was worked upas outlined in example 83. Yield 1 g (41%); brown solid; mp 175° C.; MS:462.0 (M+H)⁺

Starting from4(4-butoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carborylicacid (900 mg, 1.95 mmol) and following the procedure outlined in example83,200 mg of4-(4-butoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylicacid hydroxyamide was isolated as a HCl salt, a brown powder. Yield 20%;mp 137° C.; MS: 477.0 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆):δ0.96 (t, J=7.11Hz, 3H), 1.48 (m, 2H), 1.73 (m, 2H), 2.27 (m, 2H), 2.47 (m, 2H), 2.78(m, 2H), 3.35 (m, 2H), 3.77 (s, 2H), 4.08 (t, J=6.3 Hz, 3H), 4.32 (s,2H), 7.03 (t, 2H), 7.15 (m, 3H), 7.36 (t, J=7.8 Hz, 1H), 7.64 (d, J=9Hz, 2H), 9.36 (s, 1H), 10.22 (s, 1H).

EXAMPLE 2614(4-Methoxy-benzenesulfonyl)-1-(4thiophen-2-yl-benzyl)-piperidine-4-carboxylicacid hydroxyamide

4-(4-Methoxy-benzenesulfonyl)-1-(4thiophen-2-yl-benzyl)-piperidinecarboxylic acid ethyl ester was prepared starting from1-(4-Bromo-benzyl)-4-(4-methoxy-benzensulfonyl)-piperidine-4 -carboxylicacid ethyl ester (3 g, 6.05 mmol) and 2-(tributylstannyl)-thiophene (6.8g, 18.14 mmol) in the presence of tetrakis palladium (0) in boilingtolune. Yield 1.58 g (52%); brown solid; mp 130° C.; MS: 500 (M+H)⁺

4(4Methoxy-benzenesulfonyl)-1-(4-thiophen-2-yl-benzyl)-piperidine-4-carboxylicacid was prepared starting from4(4methoxy-benzenesulfonyl)-1-(4-thiophen-2-yl-benzyl)-piperidine-4-carboxylicacid ethyl ester (1.3 g, 2.61 mmol) dissolved in THF:methanol (3:1 150ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked upas outlined in example 83. Yield 950 mg (77%); brown solid; mp 235° C.;MS: 471.8 (M+H)⁺

Starting from4-(4-methoxy-benzenesulfonyl)-1-(4-thiophen-2-yl-benzyl)-piperidine-4-carboxylicacid (920 mg, 1.95 mmol) and following the procedure outlined in example83, 510 mg of4-(4-methoxy-benzenesulfonyl)-1-(4-thiophen-2-yl-benzyl)-piperidine-4-carboxylicacid hydroxyamide was isolated as a HCl salt, a brown solid. Yield 50%;mp 166° C.; MS: 486.9 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ2.12-2.21 (m,2H), 2.50 (m, 2H), 2.78 (m, 2H), 3.39 (m, 2H), 3.87 (s, 3H), 4.29 (d,2H), 7.17 (m, 3H), 7.54-7.75 (m, 8H), 9.36 (s, 1H), 10.07 (s, 1H)

EXAMPLE 2624-(4-methoxy-benzenesulfonyl)-1-(4-pyridin-2-yl-benzyl)-piperidine-4-carboxylicacid hydroxyamide

4-(4-Methoxy-benzenesulfonyl)-1-(4-pyridin-2-yl-benzyl)-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method outlinedin example 261. Starting from1-(4-Bromo-benzyl)-4-4-(4-methoxy-benzensulfonyl)-piperidine-4-carboxylicacid ethyl ester (4.65 g, 9.38 mmol) and 2-(tributylstannyl)-pyridine(12.08 g, 32.8 mmol). Yield 2.79 g (60%); brown oil; MS: 495.1(M+H)⁺4-(4-Methoxy-benzenesulfonyl)-1-(4-pyridin-2-yl-benzyl)-piperidine-4-carboxylicacid was prepared starting from4-(4-methoxy-benzenesulfonyl)-1-(4-pyridin-2-yl-benzyl)-piperidine-4-carboxylicacid ethyl ester (1.83 g, 3.7 mmol) dissolved in TBF:methanol (3:1 150ml) and 10 N NaOH (10 ml). The resulting reaction mixture was worked upas outlined in example 83. Yield 1.38 g (80%); off white solid; mp 217°C.; MS: 466.9 (M+H)⁺

Starting from4-(4-methoxy-benzenesulfonyl)-1-(4-pyridin-2-yl-benzyl)-piperidine-4-carboxylicacid (1.32 g, 2.83 mmol) and following the procedure outlined in example83, 480 mg of4-(4-methoxy-benzenesulfonyl)-1-(4-pyridin-2-yl-benzyl)-piperidine-4-carboxylicacid hydroxyamide was isolated as a HCl salt, a white powder. Yield 33%;mp 214° C.; MS: 482.0 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆):δ2.30 (m, 2H),2.80 (m, 2H), 3.42 (d, J=12.5 Hz, 2H), 3.75 (m, 2H), 3.88 (s, 3H), 4.36(s, 2H), 7.15 (d, J=8.9 Hz, 2H), 7.59-7.74 (m, 4H), 7.84-7.95 (m, 3H),8.55 (d, J=8.1 Hz, 1H), 8.79 (s, 1H), 9.14 (s, 1H), 10.68 (s, 1H), 11.17(s, 1H)

EXAMPLE 2631-(3,4-Dichlorobenzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylicacid hydroxyamide

4-(4-Butoxy-benzenesulfonyl)-1-(3,4-dichloro-benzyl)-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method outlinedin example 83. Starting from (4-butoxy-benzenesulfonyl)acetic acid ethylester (13.2 g 44 mmol) (3,4-dichloro-benzyl)-bis-(2-chloro-ethyl)-amine(14.3 g, mmol). Yield 14.1 g (60%), white solid, MP 86° C.; MS: 527.9(.M+H)⁺

1-(3,4-dichlorobenzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylicacid was prepared starting from4-(4-Butoxy-benzenesulfonyl)-1-(3,4-dichloro-benzyl)-piperidine-4-carboxylicacid ethyl ester (14.0 g, 26.5 mmol) dissolved in THF:Methanol (100: 50ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked upas outlined in example 83. Yield 7.87 (60%); off white solid; mp 239°C.; MS: 501.9 (M+H)⁺

Starting1-(3,4-dichlorobenzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylicacid (7.7 g, 15.5 mmol) and following the procedure outlined in example83, 4.05 g of1-(3,4-dichlorobenzyl)4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylicacid hydroxyamide was isolated as a HCl salt, white solid. Yield 48%; mp256.8° C.; MS: 514.9 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ0.94 (t, 3H),1.38-1.48 (q, 2H), 1.68-1.75 (q, 2H), 2.27 (m, 4H),2.72 (m, 2H), 4.10(t, 2h), 4.24 (s, 2H), 7.12-7.15 (d, J=8.9, 2H), 7.51-7.53 (d, J=8.1,1H), 7.63-7.65 (d, J=8.8, 2H), 7.72-7.75 (d, J=9.9, 2H), 7.87 (s, 1H),9.36 (s, 1H), 10.5 (s, 1H), 11.2 (s, 1H)

EXAMPLE 264[4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-methylpiperidine-4-carboxylicacid hydroxamide

[4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-methylpiperidine-4-carboxylicacid ethyl ester was prepared according to the general method outlinedin example 83 starting from[4-(4-chloro-benzyloxy)-benzenesulfonyl]-acetic acid ethyl ester (13.79g, 37 mmol) and 4-(4-chloro-benzyloxy)-bis-(2-chloro-ethyl)-amine (8.7g, 45 mmol). Yield 10.9 (65%); brown oil; MS: 451.9 (M+H)⁺

[4-(4-Chloro-benzyloxy)-benzenesulfonyl-1-methylpiperidine-4-carboxylicacid was prepared starting from[4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-methylpiperidine-4-carboxylicacid ethyl ester (10.7 g, 24 mmol) dissolved in THF:Methanol (75:75 ml)and 10 N NaOH (20 ml). The resulting reaction mixture was worked up asoutlined in example 83. Yield 4.9 g (50%); off white solid; MS: 426.2(M+H)⁺

Starting from[4(4-Chloro-benzyloxy)-benzenesulfonyl-1-methylpiperidine-4-carboxylicacid (4.9 g, 12 mmol) and following the procedure outlined in example83, 1.2 g of[4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-methylpiperidine-4-carboxylicacid hydroxamide was isolated as a HCl salt, off white solid. Yield 24%;mp 117.8° C.; MS: 438.9 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆):δ2.2 (m, 2H),2.49 (m, 4H), 2.5 (s, 3H), 2.6 (m, 2H), 5.2 (s, 2H), 7.25-7.23 (d,t=8.7, 2H), 7.5 (d, t=2.7, 4H), 7.68-7.71 (d, t=9.6, 2H), 9.33 (s, 1H),10.11 (s, 1H)

EXAMPLE 2654-(4-Butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)-piperidine-4-carboxylicacid hydroxamide

4-(4-Butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method outlinedin example 83 starting from 4-(4-butoxy-benzenesulfonyl)-acetic acidethyl ester (10.1 g, 34 mmol) and1-(3-phenoxy-benzyl)-bis-(2-chloro-ethyl)-amine (18 g, 50 mmol). Yield8.9 (49%); brown oil; MS: 552.1 (M+H)⁺

4-(4-Butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)-piperidine-4-carboxylicacid was prepared starting from4-(4butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)-piperidine-4-carboxylicethyl ester (10.7 g, 24 mmol) dissolved in TIF:Methanol (75:50 ml) and10 N NaOH (20 ml). The resulting reaction mixture was worked up asoutlined in example 83. Yield 5.0 g (76%); off white solid; MS: 524.3(M+H)⁺

Starting from4-(4Butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)-piperidine-4-carboxylicacid (5.9 g, 11 mmol) and following the procedure outlined in example83, 0.39 g of4-(4-butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)-piperidine-4-carboxylicacid hydroxamide was isolated as a HCl salt, tan solid. Yield 11%; mp92.5° C.; MS: 539.1 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆):δ0.93-0.97 (t,J=3.6, 3H), 1.49 (m, 2H), 1.73 (m, 2H), 2.51 (m, 4H), 4.09 (t, 2H), 4.29(bs, 2H), 7.06-7.10 (d, J=12, 2H), 7.13-7.15 (m, 3H), 7.39-7.42 (d, 2H),7.63-7.66 (d, 2H), 9.50 (s, 1H), 9.98 (s, 1H)

EXAMPLE 266[4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-(4-methylbenzyl)-piperidine-4-carboxylicacid hydroxamide

[4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-(4-methylbenzyl)-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method outlinedin example 83 starting from[1-(4-chloro-benzyloxy)-benzenesulfonyl]-acetic acid ethyl ester (5.47g, 15 mmol) and 1-(4-methyl-benzyl)-bis-(2-chloro-ethyl)-amine (5.23 g,18 mmol). Yield 8.0 (96%); brown oil; MS: 542.0 (M+H)

[4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-(4-methylbenzyl)-piperidine-4-carboxylicacid was prepared starting from[4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-(4-methylbenzyl)-piperidine-4-carboxylicacid ethyl ester (7.9 g, 124 mmol) dissolved in THF:Methanol (50: 50 ml)and 10 N NaOH (20 ml). The resulting reaction mixture was worked up asoutlined in example 83. Yield 4.6g (61%); off white solid, mp 204° C.;MS: 514.2 (M+H)⁺

Starting from[4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-(4-methylbenzyl)-piperidine-4-carboxylicacid (4.2 g, 8 mmol) and following the procedure outlined in example 83,1.3 g of[4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-(4-methylbenzyl)-piperidine-4-carboxylicacid hydroxamide was isolated as a HCl salt, yellow solid. Yield 29%; mp172° C.; MS: 528.9 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆): δ

EXAMPLE 2674-(4Butoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylicacid hydroxamide

4-(4Butoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method outlinedin example 83 starting 4-(4-Butoxy-benzenesulfonyl)-acetic acid ethylester (5.47 g, 15 mmol) and1-(4methyl-benzyl)-bis-(2-chloro-ethyl)-amine (15.3 g, 51 mmol). Yield10.1 (57%); white solid, MP 93° C.; MS: 474.1 (M+H)⁺

4-(4-Butoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylicacid was prepared starting from4-(4-Butoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylicethyl ester (10.0 g, 22 mmol) dissolved in THF:Methanol (50:50 ml) and10 N NaOH (20 ml). The resulting reaction mixture was worked up asoutlined in example 83. Yield 7.2 g (72%); off white solid, mp 244° C.;MS: 446.3 (M+H)⁺

Starting from4(4-Butoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylicacid (6.6 g, 1.5 mmol) and following the procedure outlined in example83, 2.06 g of4-(4-Butoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylicacid hydroxamide was isolated as a HCl salt, yellow solid. Yield 28%; mp137° C.; MS: 461.3 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆):δ0.91-0.964 (t,J=7.3, 3H), 1.41 (m, 2H), 1.70 (m, 4H), 1.79 (t, s, 3H), 2.52 (m, 2H),2.76 (m, 2H), 3.33 (bd, 2H), 4.10 (t, 2H), 4.22 (d, 2H), 7.12-7.14 (d,J=8.7, 2H), 7.25-7.28 (d, J=8.1, 2H), 7.42-7.45 (d, J=7.8, 2H),7.63-7.65 (d, J=8.7, 2H), 10.31 (s, 1H), 10.75 (bs, 1H)

EXAMPLE 2684(4-Butoxy-benzenesulfonyl)-1-(4cyano-benzyl)-piperidine-4-hydroxamidecarboxylic acid hydroxamide

4-(4-Butoxy-benzenesulfonyl)-1-(4-cyano-benzyl)-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method outlinedin example 83 starting 4-(Butoxy-benzenesulfonyl)-acetic acid ethylester (5.29 g, 17.6 mmol) and1-(4-cyano-benzyl)-bis-(2-chloro-ethyl)-amine (6.19 g, 21 mmol). Yield6.8 g (80%); tan oil; MS: 485.0 (M+H)⁺

4(4Butoxy-benzenesulfonyl)-1-(4cyanobenzyl)-piperidine-4-carboxylic acidwas prepared starting from4-(4-Butoxy-benzenesulfonyl)-1-(4-cyano-benzyl)-piperidine-4-carboxylicethyl ester (10.0 g, 124 mmol) dissolved in THF:Methanol (75:50 ml) and10 N NaOH (20 ml). The resulting reaction mixture was worked up asoutlined in example 83. Yield 0.7 g (11%); off white solid; MS: 456.0(M+H)⁺

Starting from4-(4-Butoxy-benzenesulfonyl)-1-(4-cyanobenzyl)-piperidine-4-carboxylicacid (0.600 g, 1.2 mmol) and following the procedure outlined in example83, 0.21 g of4-(4-Butoxy-benzenesulfonyl)-1-(4-cyano-benzyl)-piperidine-4-carboxylicacid hydroxamide was isolated as a HCl salt, off white solid. Yield 34%; mp 241.6° C.; MS: 472.0 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆):δ0.915-0.964 (t, J=7.2, 3H), 1.51 (q, 2H), 1.75 (q, 2H), 2.27 (m, 2H),2.49 (m, 4H), 4.11-4.19 (t, 2H), 4.37 (s, 1H), 7.12-7.15 (d, J=8.7, 2H),7.63-7.66 (d, J=9, 2H), 7.72-7.74 (d, J=7.8, 2H), 9.36 (s, 1H), 10.23(s, 1H), 11.16 (s, 1H)

EXAMPLE 2694-(4-Butoxy-benzenesulfonyl)-1-pyridin-4-ylmethyl-piperidine-4-carboxylicacid hydroxamide

4-(4-Butoxy-benzenesulfonyl)-1-pyridin-4-ylmethyl-piperidine-4-carboxylicacid ethyl ester was prepared according to the general method outlinedin example 83 starting, with 4-(4-Butoxy-benzenesulfonyl)-acetic acidethyl ester (6.0 g, 20.0 mmol) andpyridin-4-ylmethyl-bis-(2chloro-ethyl)-amine. (4.89 g, 21 mmol). Yield4.5 (48%); Brown oil; MS: 461.0 (M+H)⁺

4-(4-Butoxy-benzenesulfonyl)-1-pyridin-4-ylmethyl-piperidine-4-carboxylicacid was prepared starting from4-(4-Butoxy-benzenesulfonyl)-1-pyridin-4-ylmethyl-piperidine-4-carboxylicacid ethyl ester (3.0 g, 6.5 mmol) dissolved in THF:Methanol (75:50 ml)and 10 N NaOH (20 ml). The resulting reaction mixture was worked up asoutlined in example 83. Yield 1.2 g (42%); off white solid; MS: 433.0(M+H)⁺

Starting from4-(4-Butoxy-benzenesulfonyl)-1-pyridin-4-ylmethyl-piperidine-4-carboxylicacid (0.864 mg, 2.0 mmol) and following the procedure as outlined inexample 83, 600 mg of4-(4-Butoxy-benzenesulfonyl)-1-pyridin-4-ylmethyl-piperidine-4-carboxylicacid hydroxyamide was isolated as a HCl salt, off white solid. Yield67%; mp 118° C.; MS: 447.9 (M+H)⁺; 1H NMR (300 MHz, DMSO-d6): d0.94 (t,3H), 1.11 (t, 1H), 1.23 (t, 1H), 1.44 (m, 1H), 1.73 (m, 1H), 2.34 (m,2H), 2.78 (m, 2H), 3.10 (m, 2H), 3.38 (m, 2H), 4.08 (t, 2H), 4.42 (br s,2H), 7.13 (d, 2H), 7.64 (d, 2H), 7.94 (d, 2H), 8.82 (d, 2H), 11.2 (br s,1H), 11.4 (br s, 1H).

REFERENCES

1 Rickter, L. S.; Desai, M. C. Tetrahedron Letters, 1997, 38, 321-322.

The subject compounds of the present invention were tested forbiological activity according to the following procedures.

In Vitro Gelatinase Assay

The assay is based on the cleavage of the thiopeptide substrate((Ac-Pro-Leu-Gly(2 mercapto-4 methyl-pentanoyl)-Leu-Gly-OEt), BachemBioscience) by the enzyme, gelatinase, releasing the substrate productwhich reacts calorimetrically with DTNB((5,5′-dithio-bis(2-nitro-benzoic acid)). The enzyme activity ismeasured by the rate of the color increase. The thiopeptide substrate ismade up fresh as a 20 mM stock in 100% DMSO and the DTNB is dissolved in100% DMSO as a 100 mM stock and stored in dark at room temperature. Boththe substrate and DTNB are diluted together to 1 mM with substratebuffer (50 mM HEPES pH 7.5, 5 mM CaCl₂) before use. The stock of humanneutrophil gelatinase B is diluted with assay buffer (50 mM HEPES pH7.5, 5 mM CaCl₂, 0.02% Brij) to a final concentration of 0.15 mM.

The assay buffer, enzyme, DTNB/substrate (500 μM final concentration)and vehicle or inhibitor are added to a 96 well plate (total reactionvolume of 200 μl) and the increase in color is monitoredspectrophotometrically for 5 minutes at 405 nm on a plate reader. Theincrease in OD₄₀₅ is plotted and the slope of the line is calculatedwhich represents the reaction rate. The linearity of the reaction rateis confirmed (r²>0.85). The mean (×±sem) of the control rate iscalculated and compared for statistical significance (p<0.05) withdrug-treated rates using Dunnett's multiple comparison test.Dose-response relationships can be generated using multiple doses ofdrug and IC₅₀ values with 95% CI are estimated using linear regression(IPRED, HTB). References: Weingarten, H and Feder, J.,Spectrophotometric assay for vertebrate collagenase, Anal. Biochem. 147,437-440 (1985).

In Vitro Collagenase Assay

The assay is based on the cleavage of a peptide substrate((Dnp-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMa)-NH₂), Peptide International,Inc.) by collagenase releasing the fluorescent NMa group which isquantitated on the fluorometer. Dnp quenches the NMa fluorescence in theintact substrate. The assay is run in HCBC assay buffer (50 mM HEPES, pH7.0, 5 mM Ca⁺², 0.02% Brij, 0.5% Cysteine), with human recombinantfibroblast collagenase (truncated, mw=18,828, WAR, Radnor). Substrate isdissolved in methanol and stored frozen in 1 mM aliquots. Collagenase isstored frozen in buffer in 25 μM aliquots. For the assay, substrate isdissolved in HCBC buffer to a final concentration of 10 μM andcollagenase to a final concentration of 5 μnM. Compounds are dissolvedin methanol, DMSO, or HCBC. The methanol and DMSO are diluted in HCBCto<1.0%. Compounds are added to the 96 well plate containing enzyme andthe reaction is started by the addition of substrate.

The reaction is read (excitation 340 nm, emission 444 nm) for 10 min.and the increase in fluorescence over time is plotted as a linear line.The slope of the line is calculated and represents the reaction rate.

The linearity of the reaction rate is confirmed (r²>0.85). The mean(×±sem) of the control rate is calculated and compared for statisticalsignificance (p<0.05) with drug-treated rates using Dunnett's multiplecomparison test. Dose-response relationships can be generated usingmultiple doses of drug and IC₅₀ values with 95% CI are estimated usinglinear regression (IPRED, HTB). References: Bickett, D. M. et al., Ahigh throughput fluorogenic substrate for interstitial collagenase(MMP-1) and gelatinase (MMP-9), Anal. Biochem. 212,58-64 (1993).

Procedure for Measuring TACE Inhibition

Using 96-well black microtiter plates, each well receives a solutioncomposed of 10 μL TACE (Immunex, final concentration 1 μg/mL), 70 μLTris buffer, pH 7.4 containing 10% glycerol (final concentration 10 mM),and 10 μL of test compound solution in DMSO (final concentration 1 μM,DMSO concentration <1%) and incubated for 10 minutes at roomtemperature. The reaction is initiated by addition of a fluorescentpeptidyl substrate (final concentration 100 μM) to each well and thenshaking on a shaker for 5 sec. The reaction is read (excitation 340 nm,emission 420 nm) for 10 min. and the increase in fluorescence over timeis plotted as a linear line. The slope of the line is calculated andrepresents the reaction rate. The linearity of the reaction rate isconfirmed (r²>0.85). The mean (×±sem) of the control rate is calculatedand compared for statistical significance (p<0.05) with drug-treatedrates using Dunnett's multiple comparison test. Dose-responserelationships can be generate using multiple doses of drug and IC₅₀values with 95% CI are estimated using linear regression

The results obtained following these standard experimental testprocedures are presented in the following table.

IC 50 (nM or % inhibition at 1 micromolar or 10 micromolar (*)) ExampleMMP 1 MMP 9 MMP 13 TACE 1 NT 559.6 193.3 31.62% 2 NT 10.50%  0% 403 3 NT308.9 169.4 27.43% 4 371 22.20% 17.10% 21% 5 NT 7.7 4.7 25% 6 267 21.415.6 40.43% 7 844 72.9 42.1 33% 8 NT 346 307.9 47% 9 313 107 NT 20.30%10  8% 128 64 54.75% 11 18.80% 2925 319 942 12 100 10.8 11 15.50% 13 23911 14 626 14 158 23 8 17.18% 15 285 17 4 137 16 325 9 24 180 17 238.68.9 1.4 41.00% 18 540 18.9 11.5 29.2% 19 446 95.8 4.8 33.1% 20 423 14.618.7 31% 21 318 13.2 15.3 39% 22 219 3.2 2.5 30% 23 593 7.9 4.0 40.6% 24413 20.9 31.3 47.5 25 262 26.7 8.0 NT 26 304.6 6.3 3.2 34.6 27 629 10630.1 NT 28 761 3.1 2.0 30.6% 29 297 4.3 3.6 41% 30 397 8.1 5.7 25.2% 31162 15.2 5.7 688 32 13.7 3.7 1.0 NT 33 318 53.9 18.4 23.9% 34 519.8 34.726.1 28.1% 35 455.8 233.6 48.2 44.9 36 622 83.8 20.7 826 37  9% 31.6%14.3% 87 38 48.3% 1.7% 5.8% 55.1% 39 29.4% 35.2% 26.6% 69.4 40 583 19714 160 41 100 10.8 11 15.50% 42 262 50.9 6.2 36.5 43 66.1% 34.7% 55.5%46.6% 44 47.1% 36.9% 39.5% 14.9% 45 49% 48.6% 36.7% 20.4% 46 78.9%79.12% 84.7% 1.4% 47 17.1% 12.9% 7.12% 3.3% 48 99.1% 79.1% 85.4% 51.1%49 10.1% 23.7% 54.6% NT 50 51.1 58.4 10.6 NT 51 178.1 10.4 13.1 48.14%52 139.3 7.9 9.1 NT 53 647.9 27.80% 188 52.57% 54 110 66 21 55.10% 55303 10 7 21.70% 56 299 16 12 65% 57 258 332 191 16.57% 58 211 35 397.70% 59 30.20% 447 141 24.86% 60 NT 184 NT 23.60% 61 258 38 22 17.21%62 522 174 43 669 63 156 9 3 203 64 40.90% 25.60% 36.70% 29.70% 65 100063 13 42.21% 66 1600 131 226 42.33% 67 364 2.3 43.7 690 68 297 29 27 52269 574.5 120.2 90 41.32% 70 1139 88.80% 127 764 71 1000 63 13 42.21% 72117 11 1 51.64% 73 300 141 12 20.17% 74 138.1 9.2 4.3 47.86% 75 672.383.4 32.7 23.77% 76 805 NT 500 NT 77 205.5 NT 170 NT 78 262 560 3424.58% 79 25 0.54 0.4 505 80 22.1% 26% 63.6% 191 81a 2036 230.9 43.927.1 81b 3765 154 15.7 228 82 237.6 19.4 5.1 34.5% 83 492 10.2 2.0 22984 519 8.8 2.0 213 85 450 5.8 1.5 115 86 494 16.8 1.5 222 87 368 5.0 1.6170.7 88 1329 12.8 3.1 610 89 1389 38.6 7.0 49% 90 598 10.3 2.2 71.9 911929 13.3 10.8 503 92 59.6% 649 148 9.7 93 56.3% 452 38 15.8% 94 2640138 28.6 22.9 95 3681 364 33.1 25.4% 96 4437 374 33.8 18.1 97 5109 48443.7 20.20% 98 2383 3.8 1.2 154 99 656 16.2 2.4 250 100 4729 19.1 5.339.5% 101 642 12.3 2.1 197 102 662 33.7 1.9 53% 103 1306 45.1 8.8 470104 2610 3.1 1.4 208 105 1214 44.2 4.1 50.2% 106 3788 5.1 0.9 631 107629 26.8 2.5 293 108 2896 5.4 1.7 270 109 393 2.7 2.5 386 241 48.2%* 2.715.8 277 242 1950 2 1.3 581 243 2181 1.9 1.5 506 244 3417 9.8 1.5 594245 7062 43.4 2.2 51.95%* 246 50.30%* 28.3 2.4 880 249 1412 2 1.6 270250 1717 1.6 0.8 413 251 1067 0.8 0.9 301 252 801 1.1 0.9 278 255 25583.6 1.5 565 256 10000 7.2 2.9 43.01%* 259 3160 14.3 5.3  39%* 260 14952.9 1.3 272 261 513 10.9 2.7 273 262 422 6.1 2.3 298 263 3669 20.3 5.257.70%* 264 4293 2.9 3.1 182 265 1944 9.3 7.8 1037 266 4746 6 5.7 421267 3620 5.4 2.3 508 268 2292 2.8 1.1 278 269 2071 2.2 1.4 296

Compounds prepared by solid phase synthesis Data: for Examples 110 to240

MMP 13 % MMP 13 % inhibition at TACE % Example inhibition at 0.2 μMinhibition No. MMP 1 MMP 9 0.2 μM (HTS) (manual) at 1 mM 110 75 17.6 11110 40.4 112 50 33.7 113 0 13.1 114 0 0 115 0 0 116 0 9.1 117 7 8.1 11824 16.7 119 0 7.8 120 31 19.9 121 0 6.1 122 0 3.1 123 0 2.5 124 0 0 1255 2.3 126 25 10.4 127 47 29.2 128 1.9 mM 213 nM 91 255 nM 19.31 129 9032.77 130 28 27.9 131 71 20.73 132 71 20.76 133 53 22.04 134 25 −9.31135 79 42.67 136 89 42.69 137 83 13.35 138 20 5.284 139 8 28.05 140 29−4.22 141 32 11.76 142 69 54.27 143 53 43.9 144 38 19.7 145 45 2.5 14668 7.317 147 73 11.95 148 15 43.46 149 13 4.408 150 54 1.818 151 6 5.927152 9 10.03 153 12 11.8 154 89 13.14 155 31 18.62 156 23 −2.09 157 1913.7 158 33 −7.48 159 49 5.852 160 14 −3.57 161 0 12.7 162 13 0 163 849.515 164 74 62.69 165 71 73.7 166 9 4.16 167 27 8.961 168 21 3.688

MMP 13 MMP 13 MMP 13 Exam- % inhibition % inhibition % inhibition TACE %ple at 36 nM at 0.36 mM at 3.6 mM TACE inhibition No. (HTS) (HTS) (HTS)IC₅₀ nM at 1 mM 169 28 40 72 41.7 170 32 49 90 25.5 171 31 38 48 16.6172 34 32 42 29.4 173 18 46 56 25.5 174 10 19 40 27.7 175 16 20 37 32.9176 6 5 16 26.6 177 5 1 9 38.5 178 −10 74 39 26 179 12 32 60 42.7 180 1419 45 34.4 181 6 35 62 15.7 182 −9 −8 7 28.6 183 −6 12 70 34.6 184 16 2444 24.8 185 9 0 23 7.21 186 −14 −4 35 19.5 187 −14 −12 20 85.5 188 −27−24 4 16.2 189 −30 −18 −9 14. 190 −35 −28 −13 38.3 191 −45 −3 22 2.9 192−32 5 61 33.2 193 −32 −15 56 14.9 194 −17 −8 5 5.4 195 −9 −2 10 27.0 196−18 1 11 35.7 197 −33 −26 −3 17.8 198 −39 −7 15 17.1 199 −10 −7 30 −1.0200 37.9 201 50.9 202 10.6 203 32.8 204 7.75 205 84.0 206 89.8 207 −6.3208 67.7 209 31.2 210 52.2 211 20.7 212 56.0 213 −17.5 214 11.03 215 89560.12 216 2.49 217 55.1 218 380 68.7 219 7.3 220 256 53.1 221 146 98.9222 212 89.3 223 226 107.3 224 404 75.0 225 96.6 114.3 226 28 22 28 2.2227 15 −16 −22 7.3 228 37 28 65 6.8 229 29 17 33 34.4 230 29 31 26 70072.1 231 23 13 5 41.6 232 30 17 42 20.8 233 33 29 46 19.8 234 26 28 4018.4 235 59 70 70 48.3 236 44 44 64 35 237 55 65 72 38.2 238 22 11 24930 54.4 239 54 74 83 45.9 240 48 51 46 40.3

Pharmaceutical Composition

Compounds of this invention may be administered neat or with apharmaceutical carrier to a patient in need thereof. The pharmaceuticalcarrier may be solid or liquid.

Applicable solid carriers can include one or more substances which mayalso act as flavoring agents, lubricants, solubilizers, suspendingagents, fillers, glidants, compression aids, binders ortablet-disintegrating agents or an encapsulating material. In powders,the carrier is a finely divided solid which is in admixture with thefinely divided active ingredient. In tablets, the active ingredient ismixed with a carrier having the necessary compression properties insuitable proportions and compacted in the shape and size desired. Thepowders and tablets preferably contain up to 99% of the activeingredient. Suitable solid carriers include, for example, calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Liquid carriers may be used in preparing solutions, suspensions,emulsions, syrups and elixirs. The active ingredient of this inventioncan be dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as water, an organic solvent, a mixture of both orpharmaceutically acceptable oils or fat. The liquid carrier can containother suitable pharmaceutical additives such a solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, colors, viscosity regulators,stabilizers or osmo-regulators. Suitable examples of liquid carriers fororal and parenteral administration include water (particularlycontaining additives as above, e.g., cellulose derivatives, preferablesodium carboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols, e.g., glycols) and their derivatives,and oils (e.g., fractionated coconut oil and arachis oil). Forparenteral administration the carrier can also be an oily ester such asethyl oleate and isopropyl myristate. Sterile liquid carriers are usedin sterile liquid form compositions for parenteral administration.

Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be utilized by, for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously. Oral administration may be either liquid orsolid composition form.

The compounds of this invention may be administered rectally in the formof a conventional suppository. For administration by intranasal orintrabronchial inhalation or insufflation, the compounds of thisinvention may be formulated into an aqueous or partially aqueoussolution, which can then be utilized in the form of an aerosol. Thecompounds of this invention may also be administered transdermallythrough the use of a transdermal patch containing the active compoundand a carrier that is inert to the active compound, is non-toxic to theskin, and allows delivery of the agent for systemic absorption into theblood stream via the skin. The carrier may take any number of forms suchas creams and ointments, pastes, gels, and occlusive devices. The creamsand ointments may be viscous liquid or semi-solid emulsions of eitherthe oil in water or water in oil type. Pastes comprised of absorptivepowders dispersed in petroleum or hydrophilic petroleum containing theactive ingredient may also be suitable. A variety of occlusive devicesmay be used to release the active ingredient into the blood stream suchas a semipermeable membrane covering a reservoir containing the activeingredient with or without a carrier, or a matrix containing the activeingredient. Other occlusive devices are known in the literature.

The dosage to be used in the treatment of a specific patient sufferingfrom a disease or condition in which MMPs and TACE are involved must besubjectively determined by the attending physician. The variablesinvolved include the severity of the dysfunction, and the size, age, andresponse pattern of the patient. Treatment will generally be initiatedwith small dosages less than the optimum dose of the compound.Thereafter the dosage is increased until the optimum effect under thecircumstances is reached. Precise dosages for oral, parenteral, nasal,or intrabronchial administration will be determined by the administeringphysician based on experience with the individual subject treated andstandard medical principles.

Preferably the pharmaceutical composition is in unit dosage form, e.g.,as tablets or capsules. In such form, the composition is sub-divided inunit dose containing appropriate quantities of the active ingredient;the unit dosage form can be packaged compositions, for example packedpowders, vials, ampoules, prefilled syringes or sachets containingliquids. The unit dosage form can be, for example, a capsule or tabletitself, or it can be the appropriate number of any such compositions inpackage form.

What is claimed is:
 1. A compound according to formula I

wherein: R¹ is alkyl of 1 to 18 carbon atoms, optionally substitutedwith one or two groups selected independently from R⁵; alkenyl of 3 to18 carbon atoms having 1 to 3 double bonds, optionally substituted withone or two groups selected independently from R⁵; alkynyl of 3 to 18carbon atoms having I to 3 triple bonds, optionally substituted with oneor two groups selected independently from R⁵; aryl of 6 to 10 carbonatoms, optionally substituted with one or two groups selectedindependently from R⁵; cycloalkyl of 3 to 8 carbon atoms, optionallysubstituted with one or two groups selected independently from R⁵;saturated or unsaturated 5 to 10 membered mono or bicyclic heterocyclecontaining one heteroatom selected from O, S or NR⁷, optionallysubstituted with one or two groups selected independently from R⁵; orheteroaryl-(CH₂)₀₋₆— wherein the heteroaryl group is 5 to 6 memberedwith one or two heteroatoms selected independently from O, S, and N andmay be optionally substituted with one or two groups selectedindependently from R⁵; A is —S—, —SO— or SO₂—; R² and R³, taken with thecarbon atom to which they are attached, form a 5 to 7 memberedheterocyclic ring containing O optionally having one or two doublebonds; R⁴ is hydrogen, alkyl of 1 to 6 carbon atoms, optionallysubstituted with one or two groups selected independently from R⁵;alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionallysubstituted with one or two groups selected independently from R⁵;alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionallysubstituted with one or two groups selected independently from R⁵;phenyl or naphthyl optionally substituted with one or two groupsselected independently from R⁵; C₃ to C₈ cycloalkyl or bicycloalkyloptionally substituted with one or two groups selected independentlyfrom R⁵; saturated or unsaturated 5 to 10 membered mono or bicyclicheterocycle containing one heteroatom selected from O, S or NR⁷,optionally substituted with one or two groups selected independentlyfrom R⁵; R⁵ is H, C₇-C₁₁ aroyl, C₂-C₆ alkanoyl, C₁ to C₁₂ alkyl, C₂ toC₁₂alkenyl, C₂-C₁₂ alkynyl, F, Cl, Br, I, CN, CHO, C₁-C₆ alkoxy,aryloxy, heteroaryloxy, C₃-C₆ alkenyloxy, C₃-C₆ alkynyloxy, C₁-C₆alkoxyaryl, C₁-C₆ alkoxyheteroaryl, C₁-C₆ alkylamino-C₁-C₆ alkoxy, C₁-C₂alkylene dioxy, aryloxy-C₁-C₆ alkyl amine, C₁-₁₂ perfluoro alkyl,S(O)_(n)—C₁-C₆ alkyl, S(O)_(n)-aryl where n is 0, 1 or 2; OCOO C₁-C₆alkyl, OCOOaryl, OCONR⁶, COOH, COO C₁-C₆ alkyl, COOaryl, CONR⁶R⁶,CONHOH, NR⁶R⁶, SO₂NR⁶R⁶, NR⁶SO₂aryl, —NR⁶CONR⁶R⁶, NHSO₂CF₃,SO₂NHheteroaryl,SO₂NHCOaryl, CONHSO₂—C₁-C₆ alkyl, CONHSO₂aryl,SO₂NHCOaryl, CONHSO₂—C₁-C₆ alkyl, CONHSO₂aryl, NH₂, OH, aryl,heteroaryl, C₃ to C₈ cycloalkyl; or saturated or unsaturated 5 to 10membered mono or bicyclic heterocycle containing one heteroatom selectedfrom O, S or NR⁷, wherein C₁-C₆ alkyl is straight or branched,heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1to 3 heteroatoms selected independently from O, S or NR⁷ and aryl isphenyl or naphthyl, optionally substituted by 1 or 2 groups selectedfrom halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, orhydroxy; R⁶ is H, C₁ to C₁₈ alkyl optionally substituted with OH; C₃ toC₆ alkenyl, C₃ to C₆ alkynyl, C₁ to C₆ perfluoro alkyl, S(O)_(n)—C₁-C₆alkyl S(O)_(n) aryl where n is 0, 1 or 2; or COheteroaryl, whereinheteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1to 3 heteroatoms selected independently from O, S or NR⁷ and aryl isphenyl or naphthyl, optionally substituted by 1 or 2 groups selectedfrom halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, orhydroxy; and R⁷ is C₇-C₁₁ aroyl, C₂-C₆ alkanoyl, C₁-C₁₂ perfluoro alkyl,S(O)_(n)—C₁-C₆-alkyl, S(O)_(n)-aryl where n is 0, 1 or 2;COO—C₁-C₆-alkyl, COOaryl, CONHR⁶, CONR⁶R⁶, CONHOH, SO₂NR⁶R⁶, SO₂CF₃,SO₂NHheteroaryl, SO₂NHCOaryl, CONHSO—C₁-C₆-alkyl, CONHSO₂aryl, aryl, orheteroaryl, where aryl is phenyl or naphthyl, optionally substituted by1 or 2 groups selected independently from halogen, cyano, amino, nitro,C₁-C₆ alkyl, C₁-C₆ alkoxy, or hydroxy; and heteroaryl is a 5-10 memberedmono or bicyclic heteroaryl group having 1 to 3 heteroatoms selectedindependently from O, S or N—C₁-C₆ alkyl; alkyl of 1 to 18 carbon atoms,optionally substituted with one or two groups selected independentlyfrom R⁵; alkenyl of 3 to 18 carbon atoms having from 1 to 3 doublebonds, optionally substituted with one or two groups selectedindependently from R⁵; alkynyl of 3 to 18 carbon atoms having from 1 to3 triple bonds, optionally substituted with one or two groups selectedindependently from R⁵; arylalkyl of 7 to 16 carbon atoms, wherein arylis optionally substituted with one or two groups selected independentlyfrom R⁵; heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms andheteroaryl contains 1 or 2 heteroatoms selected from O, S or N and isoptionally substituted with one or two groups selected independentlyfrom R⁵; biphenylalkyl of 13 to 18 carbon atoms, wherein biphenyl isoptionally substituted with one or two groups selected independentlyfrom R⁵; arylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionallysubstituted with one or two groups selected independently from R⁵;cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, whereinthe cycloalkyl or bicycloalkyl group is optionally substituted with oneor two groups selected independently from R⁵; saturated or unsaturatedmono or bicyclic heterocycle containing one heteroatom selected from O,S or N—C₁-C₆ alkyl, optionally substituted with one or two groupsselected independently from R⁵; or R⁸R⁹N—C₁-C₆-alkoxyaryl-C₁-C₆-alkylwhere R⁸ and R⁹ are independently selected from C₁-C₆ alkyl or R⁸ and R⁹together with the interposed nitrogen forms a 5-7 membered saturatedheterocyclic ring optionally containing an oxygen atom, wherein the arylgroup is phenyl or naphthyl; or a pharmaceutically acceptable saltthereof.
 2. A compound according to claim 1 wherein: R¹ is alkyl of 1 to18 carbon atoms, optionally substituted with one or two groups selectedindependently from R⁵; alkenyl of 3 to 18 carbon atoms having 1 to 3double bonds, optionally substituted with one or two groups selectedindependently from R⁵; alkynyl of 3 to 18 carbon atoms having 1 to 3triple bonds, optionally substituted with one or two groups selectedindependently from R⁵; aryl of 6 to 10 carbon atoms, optionallysubstituted with one to two groups selected independently from R⁵;cycloalkyl of 3 to 8 carbon atoms, optionally substituted with one totwo groups selected independently from R⁵; saturated or unsaturated monoor bicyclic heterocycle of from 5 to 10 members containing oneheteroatom selected from O, S or NR⁷, optionally substituted with one totwo groups selected independently from R⁵; or heteroaryl-(CH₂)₀₋₆—wherein the heteroaryl group is 5 to 6 membered with one or twoheteroatoms selected independently from O, S, and N and may beoptionally substituted with one or two groups selected independentlyfrom R⁵; A is —S—, —SO— or SO₂—; R² and R³, taken with the carbon atomto which they are attached, form a 5 to 7 membered heterocyclic ringcontaining O optionally having one or two double bonds; R⁴ is hydrogen,alkyl of 1 to 6 carbon atoms, optionally substituted with one or twogroups selected independently from R⁵; alkenyl of 3 to 18 carbon atomshaving 1 to 3 double bonds, optionally substituted with one or twogroups selected independently from R⁵; alkynyl of 3 to 18 carbon atomshaving 1 to 3 triple bonds, optionally substituted with one or twogroups selected independently from R⁵; phenyl or naphthyl optionallysubstituted with one or two groups selected independently from R⁵; C₃ toC₈ cycloalkyl or bicycloalkyl optionally substituted with one or twogroups selected independently from R⁵; R⁵ is H, F, Cl, Br, I, CN, CHO,C₇-C₁₁ aroyl, C₂-C₆ alkanoyl, C₁ to C₁₂ alkyl, C₂ to C₁₂ alkenyl, C₂-C₁₂alkynyl, C₁-C₆ alkoxy, aryloxy, heteroaryloxy, C₃-C₆ alkenyloxy, C₃-C₆alkynyloxy, C₁-C₆ alkoxyaryl, C₁-C₆ alkoxyheteroaryl,C₁-C₆-alkylamino-C₁-C₆ alkoxy, C₁-C₂-alkylene dioxy, aryloxy-C₁-C₆ alkylamine, C₁-C₁₂ perfluoro alkyl, S(O)_(n)—C₁-C₆ alkyl, S(O)_(n)-aryl wheren is 0, 1 or 2; OCOO—C₁-C₆ alkyl, OCOOaryl, OCONR⁶, COOH, COO—C₁-C₆alkyl, COOaryl, CONR⁶R⁶, CONHOH, NR⁶R⁶, SO₂NR⁶R⁶, NR⁶SO₂aryl,NR⁶CONR⁶R⁶, NHSO₂CF₃, SO₂NHheteroaryl, SO₂NHCOaryl, CONHSO₂—C₁-C₆ alkyl,CONHSO₂aryl, SO₂NHCOaryl, CONHSO₂—C₁-C₆ alkyl, CONHSO₂aryl, NH₂, OH,aryl, heteroaryl, C₃ to C₈ cycloalkyl; or saturated or unsaturated 5 to10 membered mono or bicyclic heterocycle containing one heteroatomselected from O, S or NR⁷; wherein heteroaryl is a 5-10 membered mono orbicyclic heteroaryl group having 1 to 3 heteroatoms selectedindependently from O, S or NR⁷ and aryl is phenyl or naphthyl,optionally substituted by 1 or 2 groups selected independently fromhalogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, or hydroxy; R⁶is H, C₁ to C₁₈ alkyl optionally substituted with OH; C₃ to C₆ alkenyl,C₃ to C₆ alkynyl, C₁ to C₆ perfluoro alkyl, S(O)_(n) alkyl or aryl wheren is 0, 1, or 2; or COheteroaryl; wherein heteroaryl is a 5-10 memberedmono or bicyclic heteroaryl group having 1 to 3 heteroatoms selectedindependently from O, S or NR⁷ and aryl is phenyl or naphthyl,optionally substituted by 1 or 2 groups selected from halogen, cyano,amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, or hydroxy; and R⁷ is C₇-C₁₁aroyl, C₂-C₆ alkanoyl, C₁-C₁₂ perfluoro alkyl, S(O)_(n)-alkyl,S(O)_(n)-aryl where n is 0, 1 or 2; COOalkyl, COOaryl, CONHR⁶, CONR⁶R⁶,CONHOH, SO₂NR⁶R⁶,SO₂CF₃, SO₂NHheteroaryl, SO₂NHCOaryl, CONHSO₂alkyl,CONHSO₂aryl, aryl, heteroaryl; wherein C₁-C₆ alkyl is straight orbranched, heteroaryl is a 5-10 membered mono or bicyclic heteroarylgroup having 1 to 3 heteroatoms selected independently from O, S or NR⁷and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groupsselected from halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy,or hydroxy; alkyl of 1 to 18 carbon atoms, optionally substituted withone or two groups selected independently from R⁵; alkenyl of 3 to 18carbon atoms having from 1 to 3 double bonds, optionally substitutedwith one or two groups selected independently from R⁵; alkynyl of 3 to18 carbon atoms having from 1 to 3 triple bonds, optionally substitutedwith one or two groups selected independently from R⁵; arylalkyl of 7 to16 carbon atoms, wherein aryl is optionally substituted with one or twogroups selected independently from R⁵; heteroarylalkyl wherein alkyl isfrom 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatomsselected from O, S or N and is optionally substituted with one or twogroups selected independently from R⁵; biphenylalkyl of 13 to 18 carbonatoms, wherein biphenyl is optionally substituted with one or two groupsselected independently from R⁵; arylalkenyl of 8 to 16 carbon atoms,wherein aryl is optionally substituted with one or two groups selectedindependently from R⁵; cycloalkylalkyl or bicycloalkylalkyl of 4 to 12carbon atoms, wherein cycloalkyl or bicycloalkyl is optionallysubstituted with one or two groups selected independently from R⁵;saturated or unsaturated mono or bicyclic heterocycle containing oneheteroatom selected from O, S or N—C₁-C₆ alkyl, optionally substitutedwith one or two groups selected independently from R⁵;R⁸R⁹N—C₁-C₆-alkoxyaryl-C₁-C₆-alkyl where R⁸ and R⁹ are independentlyselected from C₁-C₆ alkyl or R⁸ and R⁹ together with the interposednitrogen forms a 5-7 membered saturated heterocyclic ring optionallycontaining an oxygen atom, wherein the aryl group is phenyl or naphthyl;or a pharmaceutically acceptable salt thereof.
 3. A compound accordingto claim 2 wherein R¹ is phenyl, naphthyl, alkyl of 1-18 carbon atoms orheteroaryl such as pyridyl, thienyl, imidazolyl or furanyl, optionallysubstituted with C₁-C₆ alkyl, C₁-C₆ alkoxy, C₆-C₁₀ aryloxy,heteroaryloxy, C₃-C₆ alkenyloxy, C₃-C₆ alkynyloxy, halogen; or S(O)_(n)——C₁-C₆alkyl C₁-C₆ alkoxyaryl or C₁-C₆ alkoxyheteroaryl; A is —S—, —SO—or —SO₂—; R² and R³, taken with the carbon atom to which they areattached, form a 5 to 7 membered heterocyclic ring containing Ooptionally having one or two double bonds; R⁴ is hydrogen, alkyl of 1 to6 carbon atoms, optionally substituted with one or two groups selectedindependently from R⁵; alkenyl of 3 to 18 carbon atoms having 1 to 3double bonds, optionally substituted with one or two groups selectedindependently from R⁵; alkynyl of 3 to 18 carbon atoms having 1 to 3triple bonds, optionally substituted with one or two groups selectedindependently from R⁵; phenyl or naphthyl optionally substituted withone or two groups selected independently from R⁵; C₃ to C₈ cycloalkyl orbicycloalkyl optionally substituted with one or two groups selectedindependently from R⁵; R⁵ is H, C₇-C₁₁ aroyl, C₂-C₆ alkanoyl, C₁ to C₁₂alkyl, C₂ to C₁₂ alkenyl, C₂-C₁₂ alkynyl, F, Cl, Br, I, CN, CHO, C₁-C₆alkoxy, aryloxy, heteroaryloxy, C₃-C₆ alkenyloxy, C₃-C₆ alkynyloxy,C₁-C₆ alkylamino-C₁-C₆ alkoxy, C₁-C₂ alkylene dioxy, aryloxy-C₁-C₆ alkylamine, C₁-C₁₂ perfluoro alkyl, S(O)_(n)—C₁-C₆ alkyl, S(O)_(n)-aryl wheren is 0, 1 or 2; OCOO C₁-C₆ alkyl, OCOOaryl, OCONR⁶, COOH, COO C₁-C₆alkyl, COOaryl, CONR⁶R⁶, CONHOH, NR⁶R⁶, SO₂NR⁶R⁶,NR⁶SO₂aryl,—NR⁶CONR⁶R⁶, NHSO₂CF₃, SO₂NHheteroaryl,SO₂NHCOaryl,CONHSO₂—C₁-C₆ alkyl, CONHSO₂aryl, SO₂NHCOaryl, CONHSO₂—C₁-C₆ alkyl,CONHSO₂aryl, NH₂, OH, aryl, heteroaryl, C₃ to C₈ cycloalkyl; saturatedor unsaturated 5 to 10 membered mono or bicyclic heterocycle containingone heteroatom selected from O, S or NR⁷, wherein C₁-C₆ alkyl isstraight or branched, heteroaryl is a 5-10 membered mono or bicyclicheteroaryl group having 1 to 3 heteroatoms selected independently fromO, S or NR⁷ and aryl is phenyl or naphthyl, optionally substituted by 1or 2 groups selected from halogen, cyano, amino, nitro, C₁-C₆ alkyl,C₁-C₆ alkoxy, or hydroxy; R⁶ is H, C₁ to C₁₈ alkyl optionallysubstituted with OH; C₃ to C₆ alkenyl, C₃ to C₆ alkynyl, C₁ to C₆perfluoro alkyl, S(O)_(n) alkyl or aryl where n is 0, 1 or 2; orCOheteroaryl; wherein heteroaryl is a 5-10 membered mono or bicyclicheteroaryl group having 1 to 3 heteroatoms selected independently fromO, S or NR⁷ and aryl is phenyl or naphthyl, optionally substituted by 1or 2 groups selected from halogen, cyano, amino, nitro, C₁-C₆ alkyl,C₁-C₆ alkoxy, or hydroxy; and R⁷ is C₇-C₁₁ aroyl, C₂-C₆ alkanoyl, C₁-C₁₂perfluoro alkyl, S(O)_(n)-alkyl, S(O)_(n)-aryl where n is 0, 1 or 2;COOalkyl, COOaryl, CONHR⁶, CONR⁶R⁶, CONHOH, SO₂NR⁶R⁶, SO₂CF₃,SO₂NHheteroaryl, SO₂NHCOaryl, CONHSO₂alkyl, CONHSO₂aryl, aryl, orheteroaryl; where aryl is phenyl or naphthyl, optionally substituted by1 or 2 groups selected independently from halogen, cyano, amino, nitro,C₁-C₆ alkyl, C₁-C₆ alkoxy, or hydroxy; and heteroaryl is a 5-10 memberedmono or bicyclic heteroaryl group having 1 to 3 heteroatoms selectedindependently from O, S or N—C₁-C₆ alkyl; alkyl of 1 to 18 carbon atoms,optionally substituted with one or two groups selected independentlyfrom R⁵; alkenyl of 3 to 18 carbon atoms having from 1 to 3 doublebonds, optionally substituted with one or two groups selectedindependently from R⁵; alkynyl of 3 to 18 carbon atoms having from 1 to3 triple bonds, optionally substituted with one or two groups selectedindependently from R⁵; arylalkyl of 7 to 16 carbon atoms, optionallysubstituted with one or two groups selected independently from R⁵;heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroarylcontains 1 or 2 heteroatoms selected from O, S or N and is optionallysubstituted with one or two groups selected independently from R⁵;biphenylalkyl of 13 to 18 carbon atoms, optionally substituted with oneor two groups selected independently from R⁵; arylalkenyl of 8 to 16carbon atoms, optionally substituted with one or two groups selectedindependently from R⁵; cycloalkylalkyl or bicycloalkylalkyl of 4 to 12carbon atoms, optionally substituted with one or two groups selectedindependently from R⁵; saturated or unsaturated mono or bicyclicheterocycle containing one heteroatom selected from O, S or NR—C₁-C₆alkyl, optionally substituted with one or two groups selectedindependently from R⁵; R⁸R⁹N—C₁-C₆-alkoxyaryl-C₁-C₆-alkyl where R⁸ andR⁹ are independently selected from C₁-C₆ alkyl or R⁸ and R⁹ togetherwith the interposed nitrogen forms a 5-7 membered saturated heterocyclicring optionally containing an oxygen atom, wherein the aryl group isphenyl or naphthyl; or a pharmaceutically acceptable salt thereof.
 4. Amethod of treating a pathological condition or disorder mediated bymatrix metalloproteinases in mammals which comprises administration to amammal in need thereof a therapeutically effective amount of a matrixmetalloproteinase inhibiting compound of the formula

wherein: R¹ is alkyl of 1 to 18 carbon atoms, optionally substitutedwith one or two groups selected independently from R⁵; alkenyl of 3 to18 carbon atoms having 1 to 3 double bonds, optionally substituted withone or two groups selected independently from R⁵; alkynyl of 3 to 18carbon atoms having 1 to 3 triple bonds, optionally substituted with oneor two groups selected independently from R⁵; aryl of 6 to 10 carbonatoms, optionally substituted with one or two groups selectedindependently from R⁵; cycloalkyl of 3 to 8 carbon atoms, optionallysubstituted with one or two groups selected independently from R⁵;saturated or unsaturated 5 to 10 membered mono or bicyclic heterocyclecontaining one heteroatom selected from O, S or NR⁷, optionallysubstituted with one or two groups selected independently from R⁵; orheteroaryl-(CH₂)₀₋₆— wherein the heteroaryl group is 5 to 6 memberedwith one or two heteroatoms selected independently from O, S, and N andmay be optionally substituted with one or two groups selectedindependently from R⁵; A is —S—, —SO— or SO₂—; R² and R³, taken with thecarbon atom to which they are attached, form a 5 to 7 memberedheterocyclic ring containing O optionally having one or two doublebonds; R⁴ is hydrogen, alkyl of 1 to 6 carbon atoms, optionallysubstituted with one or two groups selected independently from R⁵;alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionallysubstituted with one or two groups selected independently from R⁵;alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionallysubstituted with one or two groups selected independently from R⁵;phenyl or naphthyl optionally substituted with one or two groupsselected independently from R⁵; C₃ to C₈ cycloalkyl or bicycloalkyloptionally substituted with one or two groups selected independentlyfrom R⁵; saturated or unsaturated 5 to 10 membered mono or bicyclicheterocycle containing one heteroatom selected from O, S or NR⁷,optionally substituted with one or two groups selected independentlyfrom R⁵; R⁵ is H, C₇-C₁₁ aroyl, C₂-C₆ alkanoyl, C₁ to C₁₂ alkyl, C₂ toC₁₂ alkenyl, C₂-C₁₂ alkynyl, F, Cl, Br, I, CN, CHO, C₁-C₆ alkoxy,aryloxy, heteroaryloxy, C₃-C₆ alkenyloxy, C₃-C₆ alkynyloxy, C₁-C₆alkoxyaryl, C₁-C₆ alkoxyheteroaryl, C₁-C₆ alkylamino-C₁-C₆ alkoxy, C₁-C₂alkylene dioxy, aryloxy-C₁-C₆ alkyl amine, C₁-C₁₂ perfluoro alkyl,S(O)_(n)—C₁-C₆ alkyl, S(O)_(n)-aryl where n is 0, 1 or 2; OCOO C₁-C₆alkyl, OCOOaryl, OCONR⁶, COOH, COO C₁-C₆ alkyl, COOaryl, CONR⁶R⁶,CONHOH, NR⁶R⁶, SO₂NR⁶R⁶, NR⁶SO₂aryl, —NR⁶CONR⁶R⁶, NHSO₂CF₃,SO₂NHheteroaryl,SO₂NHCOaryl, CONHSO₂—C₁-C₆ alkyl, CONHSO₂aryl,SO₂NHCOaryl, CONHSO₂—C₁-C₆ alkyl, CONHSO₂aryl, NH₂, OH, aryl,heteroaryl, C₃ to C₈ cycloalkyl; or saturated or unsaturated 5 to 10membered mono or bicyclic heterocycle containing one heteroatom selectedfrom O, S or NR⁷, wherein C₁-C₆ alkyl is straight or branched,heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1to 3 heteroatoms selected independently from O, S or NR⁷ and aryl isphenyl or naphthyl, optionally substituted by 1 or 2 groups selectedfrom halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, orhydroxy; R⁶ is H, C₁ to C₁₈ alkyl optionally substituted with OH; C₃ toC₆ alkenyl, C₃ to C₆ alkynyl, C₁ to C₆ perfluoro alkyl, S(O)_(n)—C₁-C₆alkyl S(O)_(n) aryl where n is 0, 1 or 2; or COheteroaryl, whereinheteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1to 3 heteroatoms selected independently from O, S or NR⁷ and aryl isphenyl or naphthyl, optionally substituted by 1 or 2 groups selectedfrom halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, orhydroxy; and R⁷ is C₇-C₁₁ aroyl, C₂-C₆ alkanoyl, C₁-C₁₂ perfluoro alkyl,S(O)_(n)—C₁-C₆-alkyl, S(O)_(n)-aryl where n is 0, 1 or 2;COO—C₁-C₆-alkyl, COaryl, CONHR⁶, CONR⁶R⁶, CONHOH, SO₂NR⁶R⁶, SO₂CF₃,SO₂NHheteroaryl, SO₂NHCOaryl, CONHSO—C₁-C₆-alkyl, CONHSO₂aryl, aryl, orheteroaryl, where aryl is phenyl or naphthyl, optionally substituted by1 or 2 groups selected independently from halogen, cyano, amino, nitro,C₁-C₆ alkyl, C₁-C₆ alkoxy, or hydroxy; and heteroaryl is a 5-10 memberedmono or bicyclic heteroaryl group having 1 to 3 heteroatoms selectedindependently from O, S or N—C₁-C₆ alkyl; alkyl of 1 to 18 carbon atoms,optionally substituted with one or two groups selected independentlyfrom R⁵; alkenyl of 3 to 18 carbon atoms having from 1 to 3 doublebonds, optionally substituted with one or two groups selectedindependently from R⁵; alkynyl of 3 to 18 carbon atoms having from 1 to3 triple bonds, optionally substituted with one or two groups selectedindependently from R⁵; arylalkyl of 7 to 16 carbon atoms, wherein arylis optionally substituted with one or two groups selected independentlyfrom R⁵; heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms andheteroaryl contains 1 or 2 heteroatoms selected from O, S or N and isoptionally substituted with one or two groups selected independentlyfrom R⁵; biphenylalkyl of 13 to 18 carbon atoms, wherein biphenyl isoptionally substituted with one or two groups selected independentlyfrom R⁵; arylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionallysubstituted with one or two groups selected independently from R⁵;cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, whereinthe cycloalkyl or bicycloalkyl group is optionally substituted with oneor two groups selected independently from R⁵; saturated or unsaturatedmono or bicyclic heterocycle containing one heteroatom selected from O,S or N—C₁-C₆ alkyl, optionally substituted with one or two groupsselected independently from R⁵; or R⁸R⁹N—C₁-C₆-alkoxyaryl-C₁-C₆-alkylwhere R⁸ and R⁹ are independently selected from C₁-C₆ alkyl or R⁸ and R⁹together with the interposed nitrogen forms a 5-7 membered saturatedheterocyclic ring optionally containing an oxygen atom, wherein the arylgroup is phenyl or naphthyl; or a pharmaceutically acceptable saltthereof.
 5. A method according to claim 4 wherein the condition treatedis atherosclerosis, atherosclerotic plaque formation, reduction ofcoronary thrombosis from atherosclerotic plaque rupture, restenosis,MMP-mediated osteopenias, inflammatory diseases of the central nervoussystem, skin aging, angiogenesis, tumor metastasis, tumor growth,osteoarthrtis, rheumatoid arthritis, septic arthritis, cornealulceration, abnormal wound healing, bone disease, proteinuria,aneurysmal aortic disease, degenerative cartilage loss followingtraumatic joint injury, demyelinating diseases of the nervous system,cirrhosis of the liver, glomerular disease of the kidney, prematurerupture of fetal membranes, inflammatory bowel disease, or periodontaldisease.
 6. A method according to claim 4 wherein the condition treatedis age related macular degeneration, diabetic retinopathy, proliferativevitreoretinopathy, retinopathy of prematurity, ocular inflammation,keratoconus, Sjogren's syndrome, myopia, ocular tumors, ocularangiogenesis/neovascularization and cornmeal graft rejection.
 7. Amethod of treating a pathological condition or disorder mediated byTNF-α converting enzyme (TACE) in mammals which comprises administrationto a mammal in need thereof a therapeutically effective amount of a TACEinhibiting compound of the formula

wherein: R¹ is alkyl of 1 to 18 carbon atoms, optionally substitutedwith one or two groups selected independently from R⁵; alkenyl of 3 to18 carbon atoms having 1 to 3 double bonds, optionally substituted withone or two groups selected independently from R⁵; alkynyl of 3 to 18carbon atoms having 1 to 3 triple bonds, optionally substituted with oneor two groups selected independently from R⁵; aryl of 6 to 10 carbonatoms, optionally substituted with one or two groups selectedindependently from R⁵; cycloalkyl of 3 to 8 carbon atoms, optionallysubstituted with one or two groups selected independently from R⁵;saturated or unsaturated 5 to 10 membered mono or bicyclic heterocyclecontaining one heteroatom selected from O, S or NR⁷, optionallysubstituted with one or two groups selected independently from R⁵; orheteroaryl-(CH₂)₀₋₆— wherein the heteroaryl group is 5 to 6 memberedwith one or two heteroatoms selected independently from O, S, and N andmay be optionally substituted with one or two groups selectedindependently from R⁵; A is —S—, —SO— or SO₂—; R² and R³, taken with thecarbon atom to which they are attached, form a 5 to 7 memberedheterocyclic ring containing O optionally having one or two doublebonds; R⁴ is hydrogen, alkyl of 1 to 6 carbon atoms, optionallysubstituted with one or two groups selected independently from R⁵;alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionallysubstituted with one or two groups selected independently from R⁵;alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionallysubstituted with one or two groups selected independently from R⁵;phenyl or naphthyl optionally substituted with one or two groupsselected independently from R⁵; C₃ to C₈ cycloalkyl or bicycloalkyloptionally substituted with one or two groups selected independentlyfrom R⁵; saturated or unsaturated 5 to 10 membered mono or bicyclicheterocycle containing one heteroatom selected from O, S or NR⁷,optionally substituted with one or two groups selected independentlyfrom R⁵; R⁵ is H, C₇-C₁₁ aroyl, C₂-C₆ alkanoyl, C₁ to C₁₂ alkyl, C₂ toC₁₂ alkenyl, C₂-C₁₂ alkynyl, F, Cl, Br, I, CN, CHO, C₁-C₆ alkoxy,aryloxy, heteroaryloxy, C₃-C₆ alkenyloxy, C₃-C₆ alkynyloxy, C₁-C₆alkoxyaryl, C₁-C₆ alkoxyheteroaryl, C₁-C₆ alkylamino-C₁-C₆ alkoxy, C₁-C₂alkylene dioxy, aryloxy-C₁-C₆ alkyl amine, C₁-C₁₂ perfluoro alkyl,S(O)_(n)—C₁-C₆ alkyl, S(O)_(n)-aryl where n is 0, 1 or 2; OCOO C₁-C₆alkyl, OCOOaryl, OCONR⁶, COOH, COO C₁-C₆ alkyl, COOaryl, CONR⁶R⁶,CONHOH, NR⁶R⁶, SO₂NR⁶R⁶, NR⁶SO₂aryl, —NR⁶CONR⁶R⁶, NHSO₂CF₃,SO₂NHheteroaryl,SO₂NHCOaryl, CONHSO₂—C₁-C₆ alkyl, CONHSO₂aryl,SO₂NHCOaryl, CONHSO₂—C₁-C₆ alkyl, CONHSO₂aryl, NH₂, OH, aryl,heteroaryl, C₃ to C₈ cycloalkyl; or saturated or unsaturated 5 to 10membered mono or bicyclic heterocycle containing one heteroatom selectedfrom O, S or NR⁷, wherein C₁-C₆ alkyl is straight or branched,heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1to 3 heteroatoms selected independently from O, S or NR⁷ and aryl isphenyl or naphthyl, optionally substituted by 1 or 2 groups selectedfrom halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, orhydroxy; R⁶ is H, C₁ to C₁₈ alkyl optionally substituted with OH; C₃ toC₆ alkenyl, C₃ to C₆ alkynyl, C₁ to C₆ perfluoro alkyl, S(O)_(n)—C₁-C₆alkyl S(O)_(n) aryl where n is 0, 1 or 2, or COheteroaryl, whereinheteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1to 3 heteroatoms selected independently from O, S or NR⁷ and aryl isphenyl or naphthyl, optionally substituted by 1 or 2 groups selectedfrom halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, orhydroxy; and R⁷ is C₇-C₁₁ aroyl, C₂-C₆ alkanoyl, C₁-C₁₂ perfluoro alkyl,S(O)_(n)—C₁-C₆-alkyl, S(O)_(n)-aryl where n is 0, 1 or 2;COO—C₁-C₆-alkyl, COOaryl, CONHR⁶, CONR⁶R⁶, CONHOH, SO₂NR⁶R⁶, SO₂CF₃,SO₂NHheteroaryl, SO₂NHCOaryl, CONHSO—C₁-C₆-alkyl, CONHSO₂aryl, aryl, orheteroaryl, where aryl is phenyl or naphthyl, optionally substituted by1 or 2 groups selected independently from halogen, cyano, amino, nitro,C₁-C₆ alkyl, C₁-C₆ alkoxy, or hydroxy; and heteroaryl is a 5-10 memberedmono or bicyclic heteroaryl group having 1 to 3 heteroatoms selectedindependently from O, S or N—C₁-C₆ alkyl; alkyl of 1 to 18 carbon atoms,optionally substituted with one or two groups selected independentlyfrom R⁵; alkenyl of 3 to 18 carbon atoms having from 1 to 3 doublebonds, optionally substituted with one or two groups selectedindependently from R⁵; alkynyl of 3 to 18 carbon atoms having from 1 to3 triple bonds, optionally substituted with one or two groups selectedindependently from R⁵; arylalkyl of 7 to 16 carbon atoms, wherein arylis optionally substituted with one or two groups selected independentlyfrom R⁵; heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms andheteroaryl contains 1 or 2 heteroatoms selected from O, S or N and isoptionally substituted with one or two groups selected independentlyfrom R⁵; biphenylalkyl of 13 to 18 carbon atoms, wherein biphenyl isoptionally substituted with one or two groups selected independentlyfrom R⁵; arylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionallysubstituted with one or two groups selected independently from R⁵;cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, whereinthe cycloalkyl or bicycloalkyl group is optionally substituted with oneor two groups selected independently from R⁵; saturated or unsaturatedmono or bicyclic heterocycle containing one heteroatom selected from O,S or N—C₁-C₆ alkyl, optionally substituted with one or two groupsselected independently from R⁵; or R⁸R⁹N—C₁-C₆-alkoxyaryl-C₁-C₆-alkylwhere R⁸ and R⁹ are independently selected from C₁-C₆ alkyl or R⁸ and R⁹together with the interposed nitrogen forms a 5-7 membered saturatedheterocyclic ring optionally containing an oxygen atom, wherein the arylgroup is phenyl or naphthyl; or a pharmaceutically acceptable saltthereof.
 8. The method according to claim 7 wherein the conditiontreated is rheumatoid arthritis, graft rejection, cachexia, anorexia,inflammation, fever, insulin resistance, septic shock, congestive heartfailure, inflammatory disease of the central nervous system,inflammatory bowel disease, or HIV infection.
 9. A pharmaceuticalcomposition comprising a pharmaceutical carrier and a therapeuticallyeffective amount of a matrix metalloproteinase or TACE inhibitingcompound according to the formula

wherein: R¹ is alkyl of 1 to 18 carbon atoms, optionally substitutedwith one or two groups selected independently from R⁵; alkenyl of 3 to18 carbon atoms having 1 to 3 double bonds, optionally substituted withone or two groups selected independently from R⁵; alkynyl of 3 to 18carbon atoms having 1 to 3 triple bonds, optionally substituted with oneor two groups selected independently from R⁵; aryl of 6 to 10 carbonatoms, optionally substituted with one or two groups selectedindependently from R⁵; cycloalkyl of 3 to 8 carbon atoms, optionallysubstituted with one or two groups selected independently from R⁵;saturated or unsaturated 5 to 10 membered mono or bicyclic heterocyclecontaining one heteroatom selected from O, S or NR⁷, optionallysubstituted with one or two groups selected independently from R⁵; orheteroaryl-(CH₂)₀₋₆— wherein the heteroaryl group is 5 to 6 memberedwith one or two heteroatoms selected independently from O, S, and N andmay be optionally substituted with one or two groups selectedindependently from R⁵; A is —S—, —SO— or SO₂—; R² and R³, taken with thecarbon atom to which they are attached, form a 5 to 7 memberedheterocyclic ring containing O optionally having one or two doublebonds; R⁴ is hydrogen, alkyl of 1 to 6 carbon atoms, optionallysubstituted with one or two groups selected independently from R⁵;alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionallysubstituted with one or two groups selected independently from R⁵;alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionallysubstituted with one or two groups selected independently from R⁵;phenyl or naphthyl optionally substituted with one or two groupsselected independently from R⁵; C₃ to C₈ cycloalkyl or bicycloalkyloptionally substituted with one or two groups selected independentlyfrom R⁵; saturated or unsaturated 5 to 10 membered mono or bicyclicheterocycle containing one heteroatom selected from O, S or NR⁷,optionally substituted with one or two groups selected independentlyfrom R⁵; R⁵ is H, C₇-C₁₁ aroyl, C₂-C₆ alkanoyl, C₁ to C₁₂ alkyl, C₂ toC₁₂ alkenyl, C₂-C₁₂ alkynyl, F, Cl, Br, I, CN, CHO, C₁-C₆ alkoxy,aryloxy, heteroaryloxy, C₃-C₆ alkenyloxy, C₃-C₆ alkynyloxy, C₁-C₆alkoxyaryl, C₁-C₆ alkoxyheteroaryl, C₁-C₆ alkylamino-C₁-C₆ alkoxy, C₁-C₂alkylene dioxy, aryloxy-C₁-C₆ alkyl amine, C₁-C₁₂ perfluoro alkyl,S(O)_(n)—C₁-C₆ alkyl, S(O)_(n)-aryl where n is 0, 1 or 2; OCOO C₁-C₆alkyl, OCOOaryl, OCONR⁶, COOH, COO C₁-C₆ alkyl, COOaryl, CONR⁶R⁶,CONHOH, NR⁶R⁶, SO₂NR⁶R⁶, NR⁶SO₂aryl, —NR⁶CONR⁶R⁶, NHSO₂CF₃,SO₂NHheteroaryl,SO₂NHCOaryl, CONHSO₂—C₁-C₆ alkyl, CONHSO₂aryl,SO₂NHCOaryl, CONHSO₂—C₁-C₆ alkyl, CONHSO₂aryl, NH₂, OH, aryl,heteroaryl, C₃ to C₈ cycloalkyl; or saturated or unsaturated 5 to 10membered mono or bicyclic heterocycle containing one heteroatom selectedfrom O, S or NR⁷, wherein C₁-C₆ alkyl is straight or branched,heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1to 3 heteroatoms selected independently from O, S or NR⁷ and aryl isphenyl or naphthyl, optionally substituted by 1 or 2 groups selectedfrom halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, orhydroxy; R⁶ is H, C₁ to C₁₈ alkyl optionally substituted with OH; C₃ toC₆ alkenyl, C₃ to C₆ alkynyl, C₁ to C₆ perfluoro alkyl, S(O)_(n)—C₁-C₆alkyl S(O)_(n) aryl where n is 0, 1 or 2; or COheteroaryl, whereinheteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1to 3 heteroatoms selected independently from O, S or NR⁷ and aryl isphenyl or naphthyl, optionally substituted by 1 or 2 groups selectedfrom halogen, cyano, amino, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, orhydroxy; and R⁷ is C₇-C₁₁ aroyl, C₂-C₆ alkanoyl, C₁-C₁₂ perfluoro alkyl,S(O)_(n)—C₁-C₆-alkyl, S(O)_(n)-aryl where n is 0, 1 or 2;COO—C₁-C₆-alkyl, COOaryl, CONHR⁶, CONR⁶R⁶, CONHOH, SO₂NR⁶R⁶, SO₂CF₃,SO₂NHheteroaryl, SO₂NHCOaryl, CONHSO—C₁-C₆-alkyl, CONHSO₂aryl, aryl, orheteroaryl, where aryl is phenyl or naphthyl, optionally substituted by1 or 2 groups selected independently from halogen, cyano, amino, nitro,C₁-C₆ alkyl, C₁-C₆ alkoxy, or hydroxy; and heteroaryl is a 5-10 memberedmono or bicyclic heteroaryl group having 1 to 3 heteroatoms selectedindependently from O, S or N—C₁-C₆ alkyl; alkyl of 1 to 18 carbon atoms,optionally substituted with one or two groups selected independentlyfrom R⁵; alkenyl of 3 to 18 carbon atoms having from 1 to 3 doublebonds, optionally substituted with one or two groups selectedindependently from R⁵; alkynyl of 3 to 18 carbon atoms having from 1 to3 triple bonds, optionally substituted with one or two groups selectedindependently from R⁵; arylalkyl of 7 to 16 carbon atoms, wherein arylis optionally substituted with one or two groups selected independentlyfrom R⁵; heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms andheteroaryl contains 1 or 2 heteroatoms selected from O, S or N and isoptionally substituted with one or two groups selected independentlyfrom R⁵; biphenylalkyl of 13 to 18 carbon atoms, wherein biphenyl isoptionally substituted with one or two groups selected independentlyfrom R⁵; arylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionallysubstituted with one or two groups selected independently from R⁵;cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, whereinthe cycloalkyl or bicycloalkyl group is optionally substituted with oneor two groups selected independently from R⁵; saturated or unsaturatedmono or bicyclic heterocycle containing one heteroatom selected from O,S or N—C₁-C₆ alkyl, optionally substituted with one or two groupsselected independently from R⁵; or R⁸R⁹N—C₁-C₆-alkoxyaryl-C₁-C₆-alkylwhere R⁸ and R⁹ are independently selected from C₁-C₆ alkyl or R⁸ and R⁹together with the interposed nitrogen forms a 5-7 membered saturatedheterocyclic ring optionally containing an oxygen atom, wherein the arylgroup is phenyl or naphthyl; or a pharmaceutically acceptable saltthereof.